Question on cortisol / testosterone relationship.

[Glaim]

If ACTH signaling causes the release of the precursors for both Cortisol and Testosterone, why then is it said the two have an inverse relationship? (ie. if one is high the other is low) Or is this simply not the case?

I understand only a fraction of test is synthesized by the adrenal cortex in men, but in women it's one of the primary means.

[stat1951]

It occurs because Cortisol "trumps" testosterone (see below).

While the body can live without testosterone, it cannot live without cortisol. Excessive cortisol (especially the levels that people with Cushing's Disease or Cushing's Syndrome have) will kill you earlier in life than one's normal life expectancy would be (things like severe diabetes, severe cardivascular problems, more prone to cancers, etc., etc.)... but too little cortisol will kill you like "right now" (Adrenal Crisis or Adrenal Shock).

So if the HPA Axis is "reading" that there's too little cortisol in the body (even in cases where the HPA Axis is dysfunctional and there's actually too much cortisol), then the HPA Axis will continue frantically signalling for the secretion / production of yet more and more cortisol. And to continue to make the cortisol, the body will "steal" the "raw materials" from other hormone processes to keep producing cortisol. That includes (in males) DHEA and testosterone (also lowers the production of many neurotransmitters such as serotonin, etc.).

Hypercortisolism is literally recognized medically as one of the causes of hypogonadism.

http://www.gsdl.com/home/assessments...de/index3.html

Secondary hypogonadism can develop as a result of hypothalamic or pituitary disease, obesity, hypothyroidism or other causes. Some conditions, such as hypercortisolemia, AIDS and severe systemic illnesses, can trigger hypogonadism through a combination of both primary and secondary mechanisms.

http://www.wellmax.org/NewsPub/Stori...892607709.html

Hyperprolactinemia, hypercortisolemia, or hypothyroidism are also common...

http://www.google.com/answers/threadview?id=450553

According to the Great Smokies Diagnostic Lab, these are the causes of
hypogonadism: chronic/systemic illness, surgery, chemotherapy, infections, premature aging, testicular trauma, stress, Kleinfelter's syndrome, autoimmune damage, tobacco and alcohol abuse, sleep apnea, excessive heat, obesity,
hypercortisolism, (certain) medications, hyperthyroidism, malnutrition

http://neoteny.info/a/testosterone.html

Two mechanisms can account for a lower gland production of the hormone: -- a persisting significant rise in the levels of circulating epiniphrine could induce a drop in the plasma levels of testosterone by means of reduced testicular production, with unchanged global metabolic clearance (32); --- hypercortisolemia, under the condition that it is prolonged enough, would reduce the plasma levels of testosterone (33,34). This normal profile (hypercortisolemia, hypotestosteronemia) is described in other stress conditions (35,36) and in Cushings's syndrome (37,38,39)...

http://www.aace.com/pub/ep/199905ep.php

The mechanism of glucocorticoid-induced muscle atrophy relies on the degradation of the myosin heavy chain (catabolic effect), the most important contractile protein in muscle, associated with a decrease of its synthesis (antianabolic effect). One of the contributing factors in the development of muscle atrophy is hypogonadism that is induced by long-term glucocorticoid use.

http://www2.mcdaniel.edu/Biology/EPS...ss/stress.html

Glucocorticoids (technical name for cortisol in the body) also inhibit the testes and ovaries directly, hindering production of the male and female sex hormones testosterone, estrogen, and progesterone.

http://www.nutrition4health.org/NOHA...rdingAging.htm

Conditions which require large amounts of cortisol create a drain on our capacity to produce adequate hormones. To provide the excess cortisol needed to respond to conditions such as pain and inflammation, the body diverts the production of our sex hormones into the production of cortisol. In particular, the body "cannibalizes" our (WOMEN'S) sex hormone progesterone to make additional cortisol... This decrease in our progesterone often leaves us with low progesterone in comparison to our estrogen or testosterone and leads to conditions of "estrogen dominance" (is doing the same thing with testosterone in men - LRS)

From some general notes:

Also keep in mind that the body corrects abnormal cortisol levels by "stealing" from the sex hormones. The biochemists call this "pregnenelone steal," because pregnenelone is the precursor of BOTH cortisol and the sex hormones. Thus, abnormal cortisol by its nature causes derangements in the sex hormone balance.

Cortisol is a steroid hormone that governs catabolism (destructive) actions throughout the body. Testosterone is a steroid hormone that promotes anabolic (building) actions. Head-to-head, cortisol trumps testosterone. What controls cortisol? -- the reaction of the autonomic nervous system to acute and chronic stress...

Larry

[Glaim]

Thanks bro! That's exactly what I was looking for.

[stat1951]

Glad to have helped. Feel free to PM me if you have any personal related cortisol questions / concerns,

Larry

[Glaim]

"Two mechanisms can account for a lower gland production of the hormone: --a persisting significant rise in the levels of circulating epiniphrine could induce a drop in the plasma levels of testosterone by means of reduced testicular production, with unchanged global metabolic clearance (32); --- hypercortisolemia, under the condition that it is prolonged enough, would reduce the plasma levels of testosterone (33,34). This normal profile (hypercortisolemia, hypotestosteronemia) is described in other stress conditions (35,36) and in Cushings's syndrome (37,38,39)..."


So then, could long term use of clenbuterol, ephedrine, or even caffeine result in hypogonadism? Could the rise in caffeine intake be a culprit in terms of the rising rates of hypogonadism?

[stat1951]

Originally Posted by Glaim

So then, could long term use of clenbuterol, ephedrine, or even caffeine result in hypogonadism? Could the rise in caffeine intake be a culprit in terms of the rising rates of hypogonadism?

While anything is possible, I doubt that caffeine anyway could raise cortisol levels sufficiently to achieve a state of hypercortisolemia. Caffeine induced cortisol elevation is generally that of mild to moderate elevations (generally not over the high normal ranges) and - probably even more important - the elevation is "generally" of short-term nature.

As to Clen and ephedra (ephedrine), now that (especially if added to a long term excessive use of caffeine) might very well end up creating a situation of hypercortisolism - which could then lead to a disorder of hypogonadism.

Clenbuterol is in a class of drug known as Beta-2 Adrenergic Agonist, the same class as Ephedrine. It's normal use is as an asthma medication. The Beta-2 Agonists tend to speed up fat burning. Clenbuterol works best in short bursts, like 2 to 4 weeks. Here's the kicker, though. Basically from what I have read, if you are not using steroids you probably should not use Clenbuterol. Here's why: In addition to opening your breathing pathways and burning fat, Clen also tends to increase cortisol levels and decrease growth hormone (GH) levels. GH helps you burn fat and increases cortisol levels will make you fat. So without the 'roids to keep the cortisol in check the clen is pretty well useless as far as fat burning goes.

Also:

The effect of clenbuterol on adrenal function in rats.

The aim of this study was to evaluate whether the administration of clenbuterol causes stressful effects in rats, as reflected by the adrenal function. Anabolic doses of clenbuterol (1 mg kg-1, 99% purity) were administered orally by stomach tube daily for 45 d to female Long . Hormonal levels of cortisol and corticosterone, and histopathological analysis, were used as indicators of the adrenal function. Increased corticosterone and cortisol secretion was found in the treated group (p < 0.001), both in adrenal homogenates and peripheral blood samples, compared with control animals. Higher relative adrenal gland weight (adrenal gland-to-body weight ratio) was also found in the treated group (p < 0.01). The major histopathological finding was the presence of hyperplasia in the adrenocortical cells.
It was concluded that the administration of an anabolic dose of clenbuterol causes a hyperstimulation of adrenal gland secretion that could adversely affect animal welfare.

Analyst 1998 Dec;123(12):2521-4 (ISSN: 0003-2654)
Illera JC; Silvan G; Blass A; Martinez MM; Illera M Departamento de Fisiologia Animal, Facultad de Veterinaria, Universidad Complutense de Madrid, Spain

Also, hypercortisolism refers to a medical conditions where the HPA Axis gas become dysfunctional and is sending out the order (CRH / ACTH) to keep manufacturing cortisol... even though levels are already excessively high. It is like the feedback loop is no longer being recognized. Also... it is unfortunate to say, but actual hypercortisolism does NOT respond readily (sometimes barely at all) to OTC supplements. In fact, medical condition hypercortisolism is extremely difficult to bring under control.

Now if you simply have temporary high normal levels of cortisol or mildly elevated levels of cortisol, then there are a number of more-or-less effective OTC supplements that can be used with some degree of success (along with stopping and behaviors, negative supplements, diet elements, etc. that are helping to cause the elevations). But then those temporary mild levels of elevation would NOT be considered hypercortisolism so would not "generally" be responsible alone for one becoming hypogonadal....

IMHO.

Larry

[stat1951]

Good segments of article on Cortisol as involved with the disorder CSR (a disease of the eyes from hypercortisolism states). These are segments pulled as related more directly to elevated cortisol (some referencing actual hypercortisolism 0 and others simply the state of having mildly elevated cortisol levels of a temporary nature):

What is Cortisol?

Cortisol is a hormone secreted by the adrenal cortex which assists the body to deal with various stresses. It reduces inflammation and immune system function and triggers the breakdown of protein into sugars.

A certain amount of cortisol is necessary for life. Without cortisol even a small amount of stress will kill you. Addison's disease is a disease which causes low cortisol levels, and which is treated by cortisol replacement therapy...

CSR is associated with high cortisol levels. That is, people with high cortisol levels are more likely to suffer from CSR, and people with CSR generally have high levels of cortisol. CSR sufferers have high levels of cortisol made by their own adrenal gland (50-80% higher than the average, and outside the normal range)...

Adverse Effects of Excess Cortisol

Cortisol is a powerful chemical and has numerous adverse effects in excess. It is therefore recommended in the drug manuals that cortisone medication be taken in as small a dose as possible for as short a time as possible. A partial list of the adverse effects of cortisol follows:

1. Immune system suppression, leading to susceptibility to infection and cancer.
2. Loss of muscle tone.
3. Accumulation of body fat especially around the middle (as Bob Hope said 'middle age is when your age shows around your middle').
4. Depression and anxiety. Initially, however cortisol can produce a short term euphoric effect.
5. Increased permeability and fragility of the linings of blood vessels.
6. Loss of bone mass, leading to osteoporosis.
7. Damage to the hyppocampus, a brain area associated with memory.

It should be noted however that Cortisone mediation can be a life saver, for example with asthma, and in controlling some forms of short term but dangerous inflammation. A judgement needs to be made in each case of the dangers vs the benefits.
Controlling Cortisol Levels
Cortisol Regulation by the body

The body's control of cortisol levels is complex. The PVN area within the hypothalamus secretes a substance called CRF (corticotropin releasing factor). This is picked up by the pituitary gland which then secretes ACTH (adrenocorticotropic hormone). In turn this causes the adrenal cortex to secrete cortisol.

The hypothalamus acts as the body's stress detector and drives cortisol production in this way as a response to stress.

Negative feedback mechanisms exist between the body's cortisol levels and the pituitary and hypothalamus to keep the cortisol levels within reasonable bounds in normal circumstances. The negative feedback is more effective in controlling high cortisol that results from psychological stress than high cortisol that results from physical causes such as blood loss or illness.

One unfortunate fact about the body is its tendency to resist any change. For example if you go in a diet the body increases subjective hunger and decreases metabolic rate, thus 'helping' you not to lose weight. The same thing applies with many of the techniques to reduce cortisol levels. They may work for a while but then the body adapts and levels return towards the original values...

Factors that elevate cortisol

Drugs like caffeine and nicotine tell the hypothalamus that you are under stress, leading to increased cortisol levels, as well as increased adrenaline levels. The increase in cortisol levels from consuming 4-5 cups of coffee per day may be of the order of 50-60% and the increase is highest in people who are already prone to high levels of cortisol. There are anecdotal reports that other stimulants are also associated with CSR attacks eg ephedrine (found in decongestants and herbal weight loss preparations).o

Stress increases cortisol levels. This includes all the forms of stress described above. However the body is better able to control cortisol levels that result from psychological stress than those that result from physical stress.

Cortisone steroid drugs (such as prednisone, hydrocortisone, etc.) mimic the effect of high cortisol levels.

There is a lot of evidence that a stressful childhood leads to a permanently increase susceptibility to stress and increased CRF levels from the hypothalamus leading to higher cortisol levels. The stresses in childhood can range from separation from the mother through to physical and sexual abuse, hunger and disease. This can sensitize the hypothalamus and make it "trigger happy".

Pseudo-Cushings Syndrome

If you have high cortisol levels but do not have the tumour characteristic of Cushing's disease, your condition is likely to be labelled as "pseudo-Cushing's syndrome". The term is unfortunate because the high cortisol and the damage that results is just as real as in the 'real' thing. Most people develop some tolerance to cortisol over time, so the symptoms are not so extreme - difficulty controlling weight around the middle, a tendency to fluctuating blood sugar levels, high cholesterol and blood pressure, lack of energy, etc. Pseudo-Cushing's syndrome is often assumed to be due to excessive alcohol consumption or psychological depression or stress. However a recent study has established that a significant proportion of the population has a genetic predisposition to high cortisol levels, so it may not all be in your mind after all.

Also:

According to http://qualitycounts.com/fptheanine.htm, "Chief among the supplements with documented cortisol-controlling effects are Phosphatidylserine, Beta-sitosterol, Magnolia bark, Theanine, Epimedium, Ashwagandha and Passionflower".

(Note: Again, use of those OTC supplements would be in referencing cases of mold-to-moderate temporary cortisol elevation that were not actual hypercortisolism disorders.

Larry

[stat1951]

Further information on hypercortisolism as relates to the disorder of Pseudo Cushing's:

http://www.geocities.com/timjosling/csrpseudo.html

Specific segments...

Pseudo Cushing's Syndrome

Pseudo Cushing's Syndrome, sometimes known as psychological Cushing's syndrome, is a medical condition consisting of high Cortisol levels without any obvious physical cause.

In spite of the damaging effects of high cortisol levels this condition is almost universally untreated.

The patient is offered exhortations to reduce stress levels and so forth. Evidence is now growing that a better approach is possible.

Cortisol

Cortisol is a hormone produced by the adrenal glands. It is used by your body to moderate the body's response to stress. It is essential to life. Without cortisol, any stress would kill you. Addison's disease, a lack of cortisol caused by failure of the adrenal gland, is fatal unless treated by cortisol replacement medication.

Cortisol is part of the body's 'fight or flight' response to stress. The other part of the 'fight or flight' response to stress occurs when the hypothalamus signals the adrenal glands to output adrenaline and noradrenaline. These are the hormones that increase heart rate and blood pressure and that make you sweat when you are under stress.
Functions of Cortisol

Cortisol has many functions...

* It reeduces the level of immune response to disease, preventing auto-immune diseases and shock.
* It signals your body to burn protein for energy, and also in many people makes them hungry which is another way to increase the availability of energy.
* It reduces inflammation. This is why cortisol variants are commonly used as medications, for example in asthma and for skin complaints. Transplant patients and people with auto-immune conditions and allergies use it to reduce inflammation and immune over-reaction.
* In many other respects it moderates the body's response to stress, but these are not important for this discussion.

Adverse Effects of Cortisol

Excessive levels of cortisol are known to produce numerous effects. Not all the effects are felt in all people however.

1. Glaucoma and cataracts.
2. Central Serous Retinopathy.
3. High blood pressure particularly during stress.
4. Obesity.
5. Loss of muscle tone.
6. Reduced immune function; susceptibility to infection and cancer.
7. High cholesterol.
8. High levels of cortisol and its associated hormones are picked up by receptors in the brain and produce increased levels of anxiety and feelings of stress.
9. Damage to the hippocampus, a brain area associated with memory, particularly spatial memory.
10. Osteoporosis. This condition of loss of bone mass is very serious because it is often a broken bone that finally leads to the death of elderly people.
11. Stunted growth in children, as is commonly seen in asthmatics treated with cortisol derived medication.
12. Depression. A high proportion of depressed people have high cortisol levels.

Regulation of cortisol

Cortisol levels are controlled by a three level feedback process, with input from the hypothalamus. The hypothalamus is the body's stress detector.

The hypothalamus produces CRF. This stimulates the pituitary to produce ACTH. In turn the ACTH stimulates the adrenal gland to produce cortisol.

In response to high levels of cortisol the hypothalamus reduces its output of CRF and the pituitary reduces its output of ACTH. This causes the adrenal glands to reduce cortisol output. In this way cortisol levels are regulated.

However the down regulation of CRF can be overridden by the hypothamalus in the presence of stress, particularly physical stress.

Cortisol levels are cyclic, at two levels.

On a daily basis output is highest at wake-up time, and lowest at about midnight. The low level at night may be to allow the body to perform repair and growth activities that are impeded by cortisol. In healthy people, the daily variation is very wide. As people age, the daily fluctuation tends to reduce, and the average level tends to rise.

Cortisol levels also fluctuate over a period of hours, again quite widely. This is why blood tests for cortisol are largely useless because it you may pick a high or low moment.

In addition the cortisol level goes up in response to stress. Stress is any form of physical or psychological stress. The hypothalamus is your body's stress detector and receives input from a wide variety of organs, sense systems, and brain regions. The following are considered as stress by the hypothalamus: illness including tooth decay, pain, fatigue, psychological stress, physical or emotional conflict, excessive exercise, hunger, dehydration, thirst, jet lag and loss of blood.
Causes of High Cortisol Levels

The main cause of high cortisol levels is the use of prescribed cortisol derived medications. These are extensively used to treat inflammation.

Common examples are asthma and inflammatory skin conditions. Cortisol medications have a valuable role to play in treating excessive inflammation where this is life threatening or where short term treatment is needed to prevent inflammation from causing damage. This cortisol is prescribed to reduce the damage from sun spots, where the inflammatory response to the burn can cause additional damage to the eyes. However in my opinion cortisol derived medications are over used, and patients are often not made aware of possible side effects.

Cortisol is naturally high in situations of high stress, such as illness. Continued psychological stress can also raise levels, though after a while the body tends to reduce levels back towards normal.

Certain diseases of the hypothalamus, pituitary and adrenal glands can cause high levels of cortisol. The most common cause is a tumour. These illnesses are known as "Cushing's disease" or "Cushing's Syndrome" depending on the location of the tumour. These conditions are quite rare.

If the high cortisol is not due to an identified physical cause, it is called "pseudo-Cushing's syndrome". This is an unfortunate term, because the high cortisol is still very real.

It is true that in pseudo Cushing's syndrome the levels do not get as high as they can in tumour induced Cushing's, which can kill you. However the damage is still very real.

Excessive alcohol consumption raises cortisol levels. This is a common cause of pseudo Cushing's syndrome.

Another cause is associated with psychological symptoms. High cortisol levels are associated with depression and anxiety. It has always been assumed that the depression and anxiety caused the high cortisol levels via the hypothalamus, which is supposed to interpret the depression and anxiety as a form of stress.

Illness, abuse or neglect in childhood also cause chronically increased levels of cortisol throughout life. A sign of this is stunted growth.
Testing Cortisol Levels

It is important to have a test before trying any treatments. Otherwise you will never know if the treatments are effective.

There are two problems with testing cortisol levels.

First, levels in the blood fluctuate on an hourly and daily basis. This means that blood tests are useless for diagnosing high cortisol level, unless you have frequent blood tests over a period of 24 hours (excluding 12mn to 6 am). In some cases blood tests are useful to determine why the level is high, but I would not recommend having a blood test as a screening test.

As a result, the only useful screening tests is a 24 hour urine cortisol test. You collect urine for 24 hours precisely and the total cortisol derivatives produced gives an indication of the level.

The second problem is that cortisol levels vary widely in normal circumstances, depending on the level of stress. For example in AIDS patients and other people with chronic infections, levels are high. The 'normal' levels therefore cover a wide range, but if your level is always in the high normal range this level is likely to harm you.

Ideally, you should have it tested after a bad week, due to illness or stress, and also after a good week - for example after a relaxing weekend away. That way you will get an indication of you levels fluctuate during common life events.

If you have the test only at the end of a long relaxing holiday you may get a falsely low reading.

Note that patients often ask for a test for Cushing's disease. This illness causes high cortisol levels. However it is very rare and almost all the symptoms are more commonly cause by other complaints. Most GPs will have had many people tested for Cushing's, but few or no actual cases.

So you may get some resistance from your GP. You need a medical authorisation to have the test.

Psychological Cushing's

One form of pseudo Cushing's syndrome mentioned above is associated with psychological markers.

These psychological markers include high levels of anxiety and subjective stress levels. Depression is also very strongly linked to high cortisol levels.

A form of personality, called the "type A personality" is associated with high cortisol levels. The popular impression of the type A person is of a high flying businessman. Actually a type A person is better described as highly conscientious, anxious, meticulous, methodical, reliable, organised, punctual and susceptible to illness.

Previously it was thought that the psychological condition caused the high cortisol. However recent evidence suggests the contrary:

1. Psychological techniques have been found to be somewhat ineffective in reducing cortisol levels in these circumstances. If the real problem were psychological, you would expect psychological techniques to be effective.
2. A Swedish study found that there is a genetic link to high cortisol levels, affecting about 14% of the population.
3. Receptors in the brain have been shown to pick up CRF, ACTH and cortisol levels and researchers have been able to turn subjects' perceived stress levels up and down by disabling these receptors.

There is an unfortunate tendency among some GPs to dismiss anything that cannot be diagnosed or explained as psychological. In many cases an organic cause of the problem is later found.

The brain receptor studies provide a mechanism for high stress hormone levels to produce the type A personality. If your body over-reacts to any stress, and this makes you feel anxious and tense, you are likely to try and avoid stress. Thus is a type A person born: never late to the airport because they find it too stressful to be late.

Causes of Psychological Cushing's

As mentioned above it appears many people have a genetic predisposition to high cortisol levels.

In addition life circumstances can lead to high cortisol levels. Stress in early childhood such as illness or abuse or neglect has been shown to lead to a chronic life long hyper reactivity to any form of stress, which leads to high levels of cortisol in adulthood.

In addition chronic stress of any kind will produce high cortisol levels and the frequent accompanying symptoms of anxiety, depression and heightened feelings of psychological stress. This will occur regardless of whether the stress is physical or psychological.

Anti-depressants have been shown to reduce cortisol levels. However these often have adverse side effects, and many are addictive.

Other drugs exist to control cortisol levels or its impact on the body. But unfortunately these drugs cause levels of CRF and ACTH to increase, as a result of the body's feedback mechanisms. So they are not used unless absolutely necessary.

Many people with high cortisol levels do use anti-depressants and anti-anxiety medications.

While Cushing's Syndrome and Cushing's Disease are more rare than Pseudo Cushing's or simple hypercortisolism, they are disorders of sufficient concerns that if one has a hypercortisol condition that they should always request that their Endo follow through with appropriate testing to insure whether or not they may have one of those two, CD or CS....

CD is a disorder where the HPA Axis breakdown is occurring at the Pituitary gland and that an offending tumor exists there - almost always - benign - that is sending the "more and more and more" signals; while CS is a disorder where the HPA Axis dysfunction is at the adrenal level - usually - with a tumor of the adrenal gland - usually benign but sometimes not - causing that "more and more and more" message to be sent, on a rare occasion CS will be due to a small-cell ACTH-secreting cancer somewhere in the body that is causing that message to be sent... treatment of preference is to locate and surgically remove the offending tumor.

Larry