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.
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.
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 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.
DHEA is the biological daughter of pregnenolone. It is a weak androgenic hormone made in large amounts in the adrenal glands of both sexes. DHEA is a precursor of testosterone, estrogen, and corticosteroids. Their actions are similar, but generally, DHEA is more potent than pregnenolone. Energy generation appears to be more intense.
DHEA is commonly used as a hormone replacement therapy for energy enhancement and anti-aging. Supplementation with DHEA can improve well-being, energy levels, moods, and libido for normal healthy people. Dosages of 15 to 25 mg of pregnenolone and 25 to 50 mg DHEA seem to do the trick in many women as it can bring them a renewed sense of well-being. Men are less hormone sensitive and the results may not be as evident. For men, direct testosterone precursors such as androstenedione (and its metabolite androstenediol) may be more effective. These protocols, however, only apply to healthy individuals and not to those who are afflicted with Adrenal Fatigue.
DHEA is also widely used in Adrenal Fatigue. Their actions tend to mimic pregnenolone, but amplified, both in terms of desired results and side effects. Therefore, DHEA use should be judicious, as different doses appear to do different things. DHEA does not convert into progesterone; rather it converts into estrogen and testosterone. High dosages (100 to 200 mg or more) can lead to a repartitioning of body mass as a result of the conversion of the DHEA into more androgenic steroid hormones. Significant side effects are similar to those of pregnenolone, only more severe. Hair loss and acne are particularly common.
Even low dose DHEA can be problematic, as it tends to be quite stimulatory for those people with advanced adrenal weakness. In particular, those in Stage 3 (Adrenal Exhaustion) tend to react strongly even at minute dosage. Additional side effects such as severe anxiety, feeling jittery, and PMS are common and they seem to be more prevalent in women.
Since DHEA is a slight mood elevator, it can potentially clash with anti-depressants. Theoretically, the dosage of anti-depressants can be lowered if DHEA is taken. People on cholesterol lowering drugs as well as blood thinning medications, such as Coumadin, may need to watch their medications, as well as their requirements, because the amounts required to be taken may well be reduced since DHEA has both a cholesterol lowering and blood thinning effect. Studies have shown that DHEA also reduces appetite and this means that those who want to lose weight may benefit from DHEA, and those who are already on weight reduction pills may need less.
One interesting thing about DHEA is that it is not regulated by a negative feedback loop in the body. In other words, taking DHEA supplements will not suppress the production of these hormones or cause the adrenals to rest and result in atrophy from disuse. Theoretically, no “resting period” is required, although it may be a good practice to have a resting cycle of a few weeks for every few months of therapy.
Commercial DHEA products are made from diosgenin, an extract from the Mexican wild yam of the Dioscorea family. Biochemists can convert diosgenin to DHEA by engineering a series of chemical conversions, but such conversion will only happen in the laboratory and not in the human body. Therefore, ingestion of Dioscorea plant extracts cannot possibly lead to the formation of DHEA inside the body. DHEA should be used under professional guidance in the Adrenal Fatigue setting. Dosage determination can be tricky as it is not straightforward. Special attention needs to be paid to the many possible side effects similar to those of pregnenolone.
Depending on the stage of Adrenal Fatigue and on each person’s constitution, the blood or saliva DHEA level can increase while Adrenal Fatigue is in progression instead of going into gradual decline. Serum absolute levels are generally not very helpful due to inconsistent clinical correlation. From the Adrenal Fatigue perspective, DHEA should be viewed in conjunction with total cortisol. DHEA is an anabolic hormone (a building up hormone) while cortisol is a catabolic hormone (for breaking down tissues). The absolute DHEA level by itself in the Adrenal Fatigue context has little meaning. If the total cortisol to DHEA ratio is high, then there will be excessive cortisol relative to DHEA. That points to a body in a catabolic state.
The most important anti-stress hormone in the body is cortisol and it is produced in the adrenal cortex. Cortisol protects the body from excessive Adrenal Fatigue by:
- Normalizing blood sugar level Cortisol increases the blood sugar level in the body, thus providing the energy needed by the body to physically escape the threat of injury in order to survive. Cortisol works in tandem with insulin, which is released from the pancreas, to provide adequate glucose to the cells for energy. More energy from any source is required when the body is under stress, and cortisol is the hormone that makes this happens. In Adrenal Fatigue, more cortisol is secreted during the early stages but in the later stages of Adrenal Fatigue (when the adrenal glands become exhausted), cortisol output is reduced.
- Anti-inflammation Response Cortisol is a powerful anti-inflammatory agent. When we have a minor injury or a muscle strain, our body’s inflammatory cascade is initiated, leading to swelling and redness commonly seen when an ankle is sprained or when there is an insect bite. Cortisol is secreted by the body as part of its anti-inflammatory response and its objective is to remove and prevent swelling and redness in nearly all tissues. These anti-inflammatory responses will prevent mosquito bites from getting bigger, bronchial stress, and eyes from swelling shut due to allergies and Adrenal Fatigue.
- Immune System Suppression People with high cortisol levels are very much weaker from the immunological point of view. Cortisol influences most cells that participate in the body’s immune reaction, especially white blood cells. In particular, cortisol suppresses white blood cells, natural killer cells, monocytes, macrophages, and mast cells. Finally, cortisol also suppresses Adrenal Fatigue.
- Vaso-constriction Cortisol contracts mid-size arteries. People with low cortisol levels (as in advanced stages of Adrenal Fatigue) have low blood pressure and reduced reactivity to other body agents that will constrict blood vessels. Cortisol tends to increase blood pressure that is moderated.
- Physiology of Stress People with Adrenal Fatigue cannot tolerate stress and will then succumb when faced with severe stress. As the stress level increases, progressively higher levels of cortisol will be required by the body. When the cortisol level cannot rise in response to stress, it is impossible to maintain the body in its optimum stress response condition and in this respect, we can conclude that stress does kill.
In short, cortisol sustains life via two opposite, but related, kinds of regulatory actions: releasing and activating the existing defense mechanisms of the body, while shutting down and modifying the same mechanisms to prevent them.
Cortisol production from the adrenal glands is controlled via the hypothalamus-pituitary-adrenal (HPA) axis. There is an existing negative feedback loop that governs the amount of adrenal hormones that are being secreted under normal circumstances in normal people. For example, the HPA axis adjusts cortisol levels according to the body’s need via a hormone called Adrenal Corticotropic Hormone (ACTH) that is secreted by the pituitary gland in response to signals from the hypothalamus. When the ACTH binds to the walls of the adrenal gland cells, a chain reaction occurs within the cells, leading to the release of cholesterol where it is manufactured into pregnenolone, the first hormone in the adrenal cascade. After this, cortisol is released into the blood stream where it travels in the circulatory system to all parts of the body and back to the hypothalamus.
Cortisol and ACTH are not secreted uniformly throughout the day. They follow a diurnal pattern, with the highest level secreted at around 8:00 a.m., after which there is a gradual decline throughout the day. Episodic spikes during the day can also occur when the body is stressed or when certain foods are eaten. The cortisol level is at its lowest between midnight and 4:00 a.m. Morning cortisol is indicative of peak cortisol output. Noon cortisol is indicative of cortisol adaptability and usage. Afternoon cortisol is associated more with sugar regulation than adrenal cortex function, while evening cortisol level points to adrenal baseline function.
Cortisol level, especially in the morning, is characteristically high for those in Stages 1 and 2 Adrenal Fatigue as the adrenals are put on overdrive to produce more cortisol in order to neutralize stress. As Adrenal Fatigue progresses, cortisol output will eventually peak and then start to decline. Those people who are in Stage 3 Adrenal Fatigue invariably face a low cortisol level in the morning. After this time, the body’s cortisol output for the rest of the day will remain low. A 24-hour saliva cortisol curve is commonly flat throughout the day in Adrenal Exhaustion (Stage 3 Adrenal Fatigue). There are many exceptions to the above generalization and this is why relying on a test result to determine the body’s cortisol level, as the sole clinical yardstick can be very misleading. For example, some patients who are Stage 2 Adrenal Fatigue can present themselves with high evening cortisol but low or normal morning cortisol. These people tend to have low energy in the morning, with alertness returning around evening time. Despite high evening cortisol, they may be able to sleep well without sleep onset insomnia that commonly plagues those with high evening cortisol. As if this is not confusing enough, some people in Stage 3 Adrenal Fatigue clinically can present with a typical Stage 1 Adrenal Fatigue cortisol curve for reasons not well understood.
Conventional physicians have been using cortisol, also known as hydrocortisone, to combat Addison’s disease for decades. The drug is widely available under the trade name Cortef. Some have advocated the use of cortisol for treating Adrenal Fatigue as well. Some physicians, notably, Dr. Jefferies in the mid 1980s, have advocated low dose cortisol as safe for long-term use. Dr. Jefferies found that as long as the adrenal hormone level is kept within the normal range, the main toxicity that a patient might experience was a slight upset stomach, due to the body not being used to having the hormone come in through the stomach. Advances in nutritional therapeutics over the years have now greatly reduced the need of using this medication in most Adrenal Fatigue situations other than in the most serious cases. Many, however, continue to use cortisol as a first line recovery medication for Adrenal Fatigue. Over-use of cortisol as an Adrenal Fatigue recovery tool is a serious concern.
There is little questionof the great benefits of cortisol for those who need it; cortisol can be a lifesaver for someone in a severe stage of Adrenal Fatigue. The gentler natural compounds such as vitamin C, vitamin B, DHEA, and pregnenolone, when dosed and delivered properly, will greatly support adrenal health. In such cases, external cortisol administration may be delayed or avoided. However, the clinical picture is anything but straight-forward.
The use of cortisol must be considered with great care. This is because the more advanced the Adrenal Fatigue the more prevalent the symptoms of intolerance. A good portion of people suffering from advanced Adrenal Fatigue actually cannot tolerate cortisol and in fact, their condition can become worse, even at low dose. Adrenal crashes may be triggered. The exact etiology is not known. Many will require a few weeks to get used to the medication, and the beneficial effect may not be immediately evident. Still worse is the issue of addiction and withdrawal symptoms, as anyone who has gone through those problems will tell you what a nightmare things can be.
Fortunately, as mentioned earlier, modern advances in nutritional therapeutics have rendered the use of cortisol unnecessary in most cases. Cortisol can be considered as a last resort. In fact, one of the key goals in Adrenal Fatigue recovery is to let the body heal itself naturally and wean off from cortisol dependency for those who have been on it long term.
Most patients find that 5 to 10 mg of Cortef in the morning, 0 to 7 1/2 mg at noon and 0 to 2 1/2 mg at 4 p.m. often work best. The actual dosage used needs to be adjusted to match the body’s need. Those who are on cortisol should slowly decrease their dosage after a few months if possible, eventually discontinuing the treatment entirely. The key to this is to rebuild the adrenal reserve first with natural compounds before titrating down cortisol dosage to avoid negative and unpleasant rebound withdrawal side effects and adrenal crashes.
There are many side effects when using cortisol. If the dose is too high, one may feel shaky and the dosage should then be lowered. If cortisol causes upset stomach, the patients should take it with meals or lower the dose. If taken too late in the day, Cortef can disrupt sleep. At a dose of over 20 mg a day, one will begin to see the more toxic side effects of cortisol. Clearly higher doses are not recommended unless the benefits do clearly outweigh the risks.
Another important function of the adrenal glands is to maintain blood volume and pressure. Low blood pressure, low blood volume, electrolyte imbalance, and dehydration are common in people suffering from Adrenal Fatigue Stage 3. In such cases, the prescription adrenal hormone, fludrocortisones (sold under the brand name Florinef) may be indicated and can be a lifesaver.
© Copyright 2012 Michael Lam, M.D. All Rights Reserved.