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Adrenal Fatigue and Hormone Therapy

Adrenal hormones are essential for life. Too much of it or too little, however, can be dangerous. Hormone replacement is commonly prescribed by physicians when presented with a patient's symptoms suggestive of adrenal insufficiency. In the early days of adrenal hormone replacement, researchers had little clue of the proper dosage or the toxicity complications. Misled by improvement in their patients' symptoms, they gave patients many times more adrenal hormone than the normal amount. Cortisol was the drug of choice. Many patients suffered toxic effects as a result and died. Long term and excessive use of cortisol have many negative side effects as well so much, so that its use as a performance enhancer in competitive sports has now been universally banned. Because of these bad experiences, researchers became frightened and avoided prescribing adrenal hormones such as cortisol whenever possible.

In addition to adrenal hormones, the use of thyroid replacement to overcome fatigue brought on by Adrenal Fatigue is a common practice. In fact, many people with Adrenal Fatigue with symptoms of low thyroid function are prescribed thyroid medications as if they suffer from primary hypothyroidism. Many continue to suffer. In the early days of thyroid hormone replacement, patients received up to many times the usual dose of thyroid hormone as well and as a result, the toxic effects could be severe.

Clearly, hormone replacement therapy in a setting of Adrenal Fatigue requires careful attention and the use of adrenal hormones needs to be put into perspective. In the right situation and using the right dose, hormone replacement can be of great benefit.

Medical science is just beginning to find out that a person can feel horrible and function poorly even with a minimal to moderate hormone deficiency that is clinically undetected by routine blood tests. This is evident in the case of Adrenal Fatigue. Adrenal hormones are under the control of the hypothalamus-pituitary-adrenal axis where over 50 hormones are involved, and dysregulation of any one can produce unpleasant symptoms. For example, low aldosterone level can lead to blood pressure irregularities and fatigue, high estrogen can trigger PMS and anxiety, and low cortisol output can lead to sugar dysregulation, hypoglycemia and sluggishness. Those in the advanced stages of Adrenal Fatigue are especially vulnerable. Unfortunately, laboratory tests and other investigative tools are not very helpful when it comes to Adrenal Fatigue due to inconsistent clinical correlation. However, good qualitative challenges can be helpful. Paying close attention to the signs and symptoms of Adrenal Fatigue is perhaps the most effective way to assess whether or not there is the need for hormone replacement. The ultimate decision as to whether or not to use hormone replacement as an Adrenal Fatigue recovery tool is best left to the professional. Due to poorly understood patho-physiological mechanisms, some trial and error in administering hormone replacement will be inevitable even in the best of hands.

Adrenal Glands 101

The adrenal glands are two small glands; each about the size of a large grape and their role in producing hormones required for optimal living is crucial. The outer adrenal cortex comprises eighty percent of the adrenal gland and is responsible for producing over 50 different types of hormones in three major classes-glucocorticoids, mineral corticoids and androgens. Without proper hormonal production and balance, it is impossible for anyone to feel good.

When the adrenals are weak, production of any or all of these hormones will be affected. Hormones can be over-produced or under produced, depending on the state of fatigue of the adrenals, and also on each person's intrinsic body constitution. For example, cortisol output in the body usually rises in Stages 1 and 2 but will subsequently fall when a person enters into Stage 3 and beyond. DHEA level tends to fall gradually as Adrenal Fatigue progresses from Stages 1 to 4. DHEA output can also be high temporarily during onset of Adrenal Fatigue. Pregnenolone output also tends to rise in early stages of Adrenal Fatigue just like cortisol before it starts to fall due to a phenomenon known as pregnenolone steal.

In addition to output considerations, we need to pay attention to how these hormones are broken down and metabolized. All steroidal hormones are metabolized to a great degree by the liver. The more advanced the Adrenal Fatigue, the more compromised the liver function generally. Hormones required for recovery from Adrenal Fatigue need to be considered not only their absolute quantity. Just as important is consideration of the overall clearance state of the body to get rid of metabolic byproducts of the various hormones. Hormone replacement therapy for people suffering from Adrenal Fatigue, whether it is in synthetic or bio-identical form, is therefore difficult and challenging. It should be undertaken only under the close supervision of an experienced health care provider after more gentle first line recovery tools have been exhausted. In other words, adrenal hormone replacement should not be considered as a first line remedy until better and gentler compounds that can get the job done without the risk of side effects, has failed. Premature use of adrenal hormonal replacement is common in most self-navigation programs, is a common mistake, and can be a major cause of recovery delay or failure. Improper use of adrenal hormonal replacement in fact can make the condition worse due to toxicity, paradoxical effects, addiction, and withdrawal complications. Worst of all, it may also trigger adrenal crashes.

Steroidal Hormone Synthesis Pathway

A steroid is a chemical substance with four carbon ring structures attached to each other in a very specific and unique fashion. Cortisol, DHEA, testosterone, pregnenolone, progesterone, and estrogen are all steroid-based hormones that chemically look very similar to each other in terms of their basic molecular structures. They are all made in the adrenals with cholesterol being the raw material. However, their actions differ markedly, with enormous differences in how they function and in the roles they play in the various chemical factories of our bodies.

The following is a simplified diagram of how the key adrenal hormones are made:

Each hormone produced acts as part of an overall orchestra of hormones where proper balance is essential for optimal adrenal function. Each hormone has an important role to play in the overall scheme of things inside the body. In addition to recognizing the sequential cascade of hormonal synthesis, it is very important to understand that pro-hormones such as pregnenolone and DHEA, which are placed naturally at the top of the cascade, are gentler as compared to down-stream hormones such as testosterone and cortisol. The more gentle the hormone, the more nurturing it is for the adrenal to make its own down-stream hormone and the less will be the side effects. Pro-hormones are less potent but contrast this with the cortisol, which is the most potent, and has the greatest potential side effects.

This paper will examine some of the most common steroidal hormone replacements and their clinical ramification in the Adrenal Fatigue setting and these hormones are: Pregnenolone, DHEA, cortisol, melatonin, testosterone, estrogen, and progesterone. Thyroid replacement will be covered separately due to its importance.

Pregnenolone

Pregnenolone is called the mother of all steroid hormones for a good reason. It is a steroid hormone at the top of the hormonal production cascade. It is also the precursor in the synthesis of female hormones such as estrogen and progesterone, mineralocorticoids such as aldosterone that is responsible for sodium regulation, glucocorticoids such as cortisol that suppresses inflammation and helps to reduce stress, and androgens such as testosterone. Pregnenolone is therefore aptly called a pro-hormone.

Back in the 1940's, when researchers started experimenting with the use of pregnenolone, they realized that it could be helpful for people who were under stress and that it could also increase energy in those who were fatigued. However, at about the same time, cortisol, another closely related hormone, was discovered and it stole the limelight, as it was far more potent. When cortisol was given to individuals with rheumatoid arthritis or other inflammatory conditions, there were outstanding short-term improvements.

During periods of stress, the output of adrenal steroids such as cortisol will increase, which will put a great demand on pregnenolone production. This may lead to pregnenolone deficiency, which in turn may lead to reduction of both glucocorticosteroids and mineralocorticoids such as cortisol and aldosterone respectively.

Numerous studies have shown the effects of pregnenolone on the body and brain. In normal people, pregnenolone will boost energy, elevate mood and improve memory and mental performance. Pregnenolone will also create a sense of well being while improving the ability to tolerate stress. Furthermore, pregnenolone has a host of other benefits, which include the ability to influence cerebral function, the female reproductive cycle, immune defenses, inflammation, mood, skin health, sleep patterns, stress tolerance, and wound healing. As an anti-aging tool, taking pregnenolone will therefore rejuvenate the entire adrenal cascade. However, in the case of Adrenal Fatigue, replacement tends to be more complex.

Some with Adrenal Fatigue find pregnenolone replacement improves their energy, vision, memory, clarity of thinking, well being, and often sexual enjoyment or libido. Some women report lessening of hot flashes or premenstrual symptoms and this is likely due to the rise of progesterone (the biological daughter of pregnenolone) reduction in estrogen dominance. Others, however, may find pregnenolone worsen existing fatigue and may even trigger adrenal crashes. Such paradoxical reactions are common. The more advanced the adrenal weakness, the more likely such experiences are common.

Part of the reason can be explained by pregnenolone's unusual response curve. Many studies have found a U-shaped distribution in the therapeutic response to pregnenolone therapy. The U-shaped distribution describes a benefit associated with low dose pregnenolone, a loss of effect with increasing dose of pregnenolone, and a second peak of benefit with higher doses of the steroid. It is unknown what dosage range is represented in either part of the U-shaped curve for humans and whether or not this curve is altered by disease.

The cells of the adrenal glands, as well as the central nervous system, synthesize pregnenolone. In Adrenal Fatigue, pregnenolone level usually stays high in early stages, but tends to be low as adrenal weakness progresses due to a phenomena known as “pregnenolone steal” as the pregnenolone level drops because the body bypasses pregnenolone production in favor of producing more down-stream hormones such as DHEA and cortisol.

Taking pregnenolone for adrenal fatigue can therefore be challenging for multiple reasons as paradoxical reaction is a major concern. In addition, one can take what appears to be an adequate dosage but will not benefit from this if the body is shunting it towards cortisol production. On the other hand, overdose is possible if too much is taken over time.

The normal starting dose is 15 mg, increasing up to 100 mg for men or women. Pregnenolone should be derived from a pharmacologically pure product and not a yam-derived "precursor.” Oral pregnenolone pills work well. Sublingual administration is an excellent option by bypassing the initial liver metabolism that occurs after swallowing an oral pill but it tends to be "spiky" and not well tolerated by those who are sensitive or in advanced s adrenal fatigue state.

Pregnenolone is converted in the body to progesterone and these two hormones have some overlapping similarities. Pregnenolone is also converted into DHEA, which, in turn may convert into androstenedione, testosterone, and estrogens. Pregnenolone supplementation may increase progesterone levels and consequently other hormones in the body (testosterone and estradiol).

Side effects include:

  • Over stimulation and insomnia - low doses can be helpful for sleep when taken in the morning. This is especially prominent in those with advanced adrenal fatigue.

  • Irritability, anger or anxiety - low doses can actually ease a person into a relaxed feeling, while higher amounts may lead to irritability. The exact reason for this is not known.

  • Acne can occur due to the probable conversion of this hormone into androgens.

  • Headaches are possible with high dosages - possible scalp hair loss if used daily for prolonged periods. Pregnenolone converts into DHEA, which in turn converts into testosterone and possibly onto DHT. Pregnenolone can also be converted into progesterone.

  • Irregular heart rhythm, heart palpitations, even when the dose is as low as 10 mg. This side effect can be serious in the elderly or in those with heart rhythm disturbances.

  • Pregnenolone may cause disturbances in the endocrine system, including changes in the menstrual cycle and problems associated with hormone sensitive diseases, or it may interact with hormone therapy such as oral contraceptives.

Due to the possible side effects, pregnenolone should be taken under the supervision of a health care professional. Do not rely on blood or saliva tests alone to determine how much pregnenolone should be taken as the clinical correlation is unreliable in Adrenal Fatigue.

Due to its antagonistic effects on the GABA receptor in the central nervous system, pregnenolone therapy may be contraindicated in some people with a history of seizures. Pregnenolone may inhibit drugs used to increase GABA activity (i.e. Neurontin); these drugs are frequently used in the treatment of epilepsy and depression.

Both pregnenolone and DHEA can be taken together for adrenal fatigue. Since some pregnenolone is converted into DHEA, the intake amount of DHEA can be lowered if both are taken together.

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