Pregnenolone For Adrenal Fatigue


Adrenal Fatigue Syndrome (AFS), also known as hypoadrenia, is a condition caused by chronic stress that is not well known among conventionally trained physicians.

Some people at high risk for the symptoms of adrenal fatigue include busy new parents, students in college or post-graduate studies and caregivers, such as nurses or family members caring for invalid relatives.

In fact, anyone is is under severe, prolonged stress, can be at risk for developing AFS. 

The symptoms of this condition are sometimes vague and difficult to recognize as a pattern that denotes a problem with adrenal output.



Signs of Adrenal Fatigue


Because of the vast influence of the adrenals on the body, symptoms of adrenal fatigue can mimic a number of disorders and isn’t always easily recognizable.

Most sources agree that adrenal fatigue symptoms include extreme fatigue, brain fog, weight gain, insulin resistance and others.

While the mere fact you feel fatigued is not necessarily indicative of adrenal fatigue, and adrenal fatigue tests aren’t always straightforward, there is evidence that high cortisol levels found in saliva are associated with reduced immune function, increased blood pressure, increased heart rate and delayed growth in children. (1)


Typical Symptoms of AFS (2)

  • Autoimmune conditions
  • Chronic fatigue (always feeling tired)
  • Brain fog
  • Hair loss
  • Hormone imbalance
  • Weakened stress response
  • Insulin resistance
  • Lightheadedness
  • Decreased sex drive/libido
  • Moodiness and irritability
  • Depression
  • Muscle or bone loss
  • Skin ailments
  • Sleep disturbances
  • Weight gain
  • Sweet and salty food cravings


These symptoms and more can be indicative of a few different disorders and are often overlooked by doctors, but more and more people are starting to realize that a combination of these could indicate the onset of adrenal fatigue.



As AFS sufferers know, these symptoms can become debilitating.

On presenting symptoms of AFS to your physician, he or she will likely focus solely on the symptoms and not on a more comprehensive viewpoint in managing your condition.




Doctors are Often Unfamiliar With Adrenal Fatigue Syndrome

Conventionally trained physicians have no problem identifying excessively high levels of cortisol as being associated with Cushing’s Disease, and low levels of cortisol being associated with Addison’s Disease.

However, these two extremes of adrenal function do not take into consideration any state in between.

Tests used for these conditions only delineate the extremely high or low levels of cortisol.

Those who have normal laboratory results but clinically symptomatic levels are ignored.




The Sub-Clinical State of Your Cortisol Level


This wide range of unusual but not clinically problematic levels of cortisol is called a subclinical state, and this is where those with AFS typically test.

AFS is difficult to identify using standard medical blood tests. The tests used to check hormones related to the adrenals are designed to pick up extremely high or low levels, and will miss hormone levels that are outside the extremes.

You may have hormone levels that are out of balance, or too low for optimal functioning, but these tests miss them.


The result is that patients are told they have normal hormone levels, or that their adrenals are functioning normally, when in fact they aren’t. Conventional medicine offers no help, or symptoms are addressed individually, with little or no relief resulting.



Treating Only the Symptoms of AFS

Efforts by conventionally trained physicians aim at the symptoms of AFS only:


  • You may be given antidepressants or anti-anxiety medications, because depression and anxiety are typical symptoms of AFS.


  • You may be given sleep medications, because insomnia is typical of AFS.


  • Pain medications may be used, because pain is part of the symptomatic picture of AFS.


  • The presence of continuing and potentially debilitating fatigue will lead your physician to suggest rest and learning to relax.


  • In severe cases, cortisol may be recommended.


… And often, none of these measures provide any significant improvement.




A More Comprehensive Approach


Treating your individual symptoms doesn’t put all of your symptoms into a picture of your overall state.

Rather than relying on an organ-specific approach to symptoms of AFS, or attempting to address symptoms individually, alternative medicine takes a more comprehensive viewpoint towards healing

A comprehensive approach takes the interrelationship of responses from different organ systems of the body into account as an important part of addressing the issue. With this approach, hormones such as pregnenolone or cortisol have a place in relieving AFS sufferers.



Hormones and Adrenal Fatigue Syndrome


Under conditions of high and continuing stress, hormone balance is very important, and pregnenolone can an important role in providing your body with the building blocks to produce the hormones it needs.



Treating AFS With Pregnenolone


One of the methods to addresses AFS may be to add a pregnenolone supplement to your “treatment toolbox,” to bring all the other hormones into balance.

In addition helping your hormones regain balance, pregnenolone supplementation has been shown to help lower cortisol, which can be very effective in addressing many of the symptoms of AFS, such as:

  • Depression
  • Hypoglycemia
  • Brain fog
  • Craving for sweets
  • Headaches
  • Fatigue
  • Nervousness
  • Concentration problems
  • Insomnia




For those who don’t enjoy reading excerpts of scientific studies –

  • you can skip this next section and scroll down to the green arrow below to continue reading.




Scientific Studies on the Effect of Prenenolone on Cortisol


These studies below demonstrate direct effects of pregnenolone in opposition to cortisol.

The mechanism of action is prevention of cortisol (bound to the GR receptor) from moving into the cell nucleus. This so-called “translocation” of the cortisol-GR bound peptide is necessary for cortisol to exert its systemic effects. By inhibiting the translocation of the cortisol-bound GR to the nucleus pregnenolone largely eliminates cortisol’s effects on the organism.

So, while pregnenolone is not a direct cortisol antagonist in the sense that it binds to the GR receptor as antagonist, it has indirect antagonist effect in the sense that it prevents cortisol from exerting any of its typical effects through activation of transcription factors in the cell nucleus/DNA.

Similar inhibitory effects on cortisol accumulation in the cell nucleus were also noted with progesterone and DHEA. However, progesterone and DHEA were not nearly as potent as pregnenolone and also the high micromolar concentrations required to observe the inhibitor effects make DHEA inconvenient as it would result in estrogen elevation.

Also, while the first study showed dose-dependent reduction by pregnenolone of cortisol accumulation in the nucleus, the second study showed that there is an optimal concentration for this effect and it is relatively low (500nM/L). This concentration can be achieved in a human with a dose of <50mg daily.


Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity. – PubMed – NCBI
“…We tested several other pharmacological agents chemically or pharmacologically related to mifepristone: GR antagonists, pregnenolone and DHEA; synthetic progestin causing abortion, levonorgestrel; MR antagonist, spironolactone [1,23].”


Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. – PubMed – NCBI
“…Immunofluorescence profiles of glucocorticoid receptors presented in Fig. 3A-C revealed that control, untreated cells, have less GR nuclear localization as judged from the intensity of immunofluorescence. Cells treated with pregnenolone for 24 hours alone showed a similar GR localization profile as observed for control untreated cells (data not shown). Interestingly, HT-22 cells treated for 20 hours with 5 mM glutamate showed very intense visualization of GR (Fig. 3B), 500 nM pregnenolone treatment for 24 hours, followed by 5 mM glutamate treatment for 20 hours remarkably decreased the nuclear localization of GR (Fig. 3C). We have calculated the relative nuclear to cytoplasmic fluorescence ratio to be 0.07, 0.08, 1.52, and 0.14 in control, pregnenolone alone treated, glutamate treated and pregnenolone followed by glutamate treated cells respectively.”

“…Glutamate is a major activator of the hypothal-amo-pituitary-adrenal (HPA) axis and is known to increase plasma levels of corticosterone via involvement of type II glucocorticoid receptor (GR) availability (17,18). Pertinent to this we observed that treatment of HT-22 cells with 5 mM glutamate for 20 hr resulted in intense nuclear localization of glucocorticoid receptor as detected by immunofluorescence technique. Pre-treatment with 500 nM pregnenolone for 24 hr followed by administration of 5 mM glutamate for 20 hr, dramatically decreased GR nuclear localization. It is of interest that like DHEA, pregnenolone directly modulates nuclear localization of GR (3). Since glucocorticoids are known to exacerbate neuronal cell death and damage (11,15), and pregnenolone exerts consistent neuroprotective effects; it is logical to assume that the neuroprotective effects of pregnenolone, are at least in part, mediated by decreasing GR nuclear localization induced by glutamate neurotoxicity. Our postulate is that pregnenolone exerts its protective action via a nuclear GR down modulation. The neuroprotective effects of pregnenolone are further supported by the recent report showing that the glucocorticoid receptor antagonist RU486 also protects against glutamate neurotoxicity in HT-22 cells.”



The Pregnenolone Steal Theory


If you have been researching pregnenolone, you may have come across a phenomena known as “the pregnenolone steal. 

This is a notion states that since all steroid hormones use pregnenolone (derived from cholesterol) as a precursor, the elevated secretion of cortisol caused by acute or chronic stress will inevitably result in less available pregnenolone to serve as a precursor for the production of DHEA and other down-stream hormones.

In other words, according to this theory, the need for cortisol synthesis “steals” pregnenolone away from other hormone pathways, reducing the potential synthesis and secretion of other necessary hormones, resulting in some of the pathophysiological changes related to stress.





Current Thinking is that the “Pregnenolone Steal” Theory is a Myth:




“While a rise in cortisol levels and a concomitant drop in DHEA(S) is one of the clinical characteristics of early and mid-stage stress progression, this phenomenon is not caused by diminished adrenal pregnenolone availability or “pregnenolone steal.” (See page 66 for the three-stage model of stress adaptation). The most obvious reason is the fact that the conversion of cholesterol to pregnenolone occurs in the mitochondria of each respective cell type (See Figure 13).

Simply put, there is no known adrenal pool of pregnenolone for one cell to steal away from another, and no known mechanism has been described that could facilitate the transfer of pregnenolone between the mitochondria of different cells (in this case, from the mitochondria of cells within the zona reticularis to those within the zona fasciculata).

Unfortunately, the most common figures used to teach steroidogenesis show a common pathway and typically do not specify the differential regulation of available enzymes between different steroidogenic tissues. This leads many to incorrectly assume there is a single “pool” of pregnenolone available for all steroid hormone synthesis within the different adrenal cortex zones.”

“…In addition, the ACTH-driven adrenal synthesis of cortisol is orders of magnitude higher than that of DHEA(S), and fluctuates radically within a 24-hour period. If there were an adrenal “pregnenolone pool” that contained enough pregnenolone precursors for elevated cortisol production in the morning (or during stress), this “pool” would then also be available for the much smaller amount of needed DHEA(S) production when cortisol synthesis drops even a little.

Finally, as decades of steroidogenesis research has shown, the control of adrenal hormone output is regulated mostly by cellspecific enzyme concentrations and external signals coming from outside the adrenal gland (See main text for specifics).

What, then, does this mean in relation to cortisol and DHEA(S) output which, when measured, appears to confirm this phenomenon? What about the role of oral pregnenolone therapy for supporting adrenal DHEA(S) production? As we will continue to reinforce throughout this guidebook, the HPA axis in general and the production of cortisol and DHEA(S) in particular, have a complex interrelationship.

While HPA axis stress and subsequent cortisol synthesis and secretion may coincide with the acceleration of reduced DHEA(S) production (i.e., a stress-induced down-regulation of DHEA(S)), this relationship is facilitated by regulatory processes (e.g., feedback inhibitions, receptor signaling, genomic regulation of enzymes, etc.), not an intra-adrenal depletion of pregnenolone as a precursor to downstream hormones.

For instance, experimentally-induced hyperglycemia and hyperinsulinemia has been shown to affect DHEA and androstenedione production in human subjects.24,25 In one study of poorly-controlled type 2 diabetic subjects with elevated cortisol and low DHEA levels, the enzyme necessary for DHEA formation in the zona reticularis (17,20 lyase) was shown to limit the production of DHEA. The enzyme activity was corrected (along with near normalization of cortisol, DHEA and DHEA-S levels) after six months of diet or pharmacotherapy to improve blood glucose control.26

Additionally, cell-culture studies suggest that under inflammatory stress (IL-4 and other cytokines), the zona reticularis will down-regulate DHEA production when ACTH is present.27,28 These and many other factors (e.g., aging) are likely the driving influenced affecting the dynamic relationship between cortisol (activated by the HPA axis) and measured DHEA and/or DHEA-S levels.”

“…As we will review later, the use of oral pregnenolone supplementation as part of a broader strategy to improve patient DHEA(S) levels (accompanied by many anecdotal reports of clinical benefits) is common. However, there is limited published data related to oral pregnenolone therapy and changes in adrenal DHEA output or in measures of serum or salivary DHEA or DHEA-S. There is, however, some limited data on the use of oral pregnenolone with apparent neurosteroid outcomes, which is covered on page 114.”




In the early stages of AFS and under continuing stress, cortisol is constantly being secreted.


As shown in the above studies, increasing pregnenolone can potentially lower cortisol levels, so that they’re closer to what would be normal for the individual.  High levels of cortisol  can be harmful to the body, and adding more pregnenolone can prevent or at least minimize their damaging effects.


In the brain, pregnenolone has a protective function. Fatigue can injure brain cells, and pregnenolone can help protects these cells from this kind of damage through its calming effect (which lowers cortisol production).

Pregnenolone can be converted into progesterone and DHEA, both protective hormones in themselves. It also supports the functioning of the thyroid and other glands.



Don’t Buy “Extract of Wild Yams”


Supplemental pregnenolone is made from wild yams grown in Mexico and southern areas of the U.S. It is molecularly identical to your body’s pregnenolone.

Be cautious about the source, though: the wild yams used in making supplemental pregnenolone contain diosgenin, a hormone precursor that is converted into pregnenolone in the lab. Your body doesn’t have the enzymes needed for this conversion., so it is important to ensure that any over the counter pregnenolone supplements you buy are actually labeled pregnenolone, and not simply extracts of wild yams. 

There are a lot of high quality options available; the Double Wood Supplements Prenenolone seems to be the best rated at the time of this posting.

Pregnenolone 100mg – Made in USA – Third Party Tested for Purity – 120 Capsules by Double Wood Supplements
Example: Double Wood Supplements Pregnenolone




Pregnenolone Cautions


Supplementation with pregnenolone can be beneficial in alleviating symptoms of AFS, but there are some side effects and contraindications to its use.

Due to the lack of solid research into the use of pregnenolone supplements, caution is suggested. Regardless of the scarcity of research, there are practitioners who do not hesitate to use the supplements. Some of these practitioners believe use of these supplements will stimulate your body into making more pregnenolone itself, even after the supplements are stopped.

Some research was conducted on the use of pregnenolone on several populations in the 1930s and 1940s. However, these investigations were replaced by research into other substances in the 1950s because of the possibility of these other substances to be patented by pharmaceutical companies. Since then, little research into the hormone has been conducted.

Like any other steroid, large doses or extended use of pregnenolone could cause some steroid-like side effects including overstimulation, insomnia, irritability, anger, anxiety, acne, headache, negative mood changes, facial hair growth, hair loss, and irregular heart rhythm.

There also may be interactions with other substances. If you’re taking estrogens, don’t take pregnenolone supplements. They will lead to too much estrogen in your system. The same is true with progestin and testosterone supplements.

In general, supplementation with pregnenolone is safe as long as it is conducted under the supervision of a well-trained physician. It is not something to be undertaken by yourself, although you may have to educate your physician so he/she can best help you.



Other Beneficial Supplements For AFS


In addition to pregnenolone, there are certain herbs, spices and essential oils that can help to fight adrenal fatigue and support your energy level and general health.



Ashwagandha, Rhodiola Rosea, Schisandra and Holy Basil (Adaptogenic Herbs)


Research indicates that adaptogen herbs may help to lower cortisol levels and mediate stress responses within the body. (3, 4, 5) By using these herbs in food preparation, you can alleviate some of the strain on your adrenal glands.





Ashwagandha is grown in India, Yemen, Nepal, and China, and the roots are collected and used in herbal medicine. Externally, the berries and leaves can be used to treat ulcers, tumors, and burns and internally the medicine combats stress, sleeplessness, hormone imbalance, and liver disease. The plant affects the body by altering the chemicals in the brain that cause stress, inflammation, immune disease, and high blood pressure.



Rhodiola Rosea


Rhodiola rosea is a herb in the rhodiola genera (Crassulaceae family) which has traditional usage as an anti-fatigue agent and adaptogen compound.

In regards to fatigue, rhodiola appears to be able to significantly reduce the effects of prolonged and minor physical exhaustion that results in fatigue. This is more related to stress and the ‘burnout’ effect, or prolonged but low intensity physical exercise.

There is some limited evidence that parameters of physical exercise can be improved with rhodiola, but this appears to be limited to untrained persons with numerous studies on trained athletes suggesting that rhodiola does not have an acute ergogenic effect.

Despite this, rhodiola appears to be highly reliable in reducing fatigue symptoms and improving symptoms of stress (and secondary to that, well-being) in persons fatigued from non-exercise related stressors.





Schisandra has a long history in Traditional Chinese Medicine (TCM). Chinese folklore says that this herb can “calm the heart and quiet the spirit.”  It is native to Russia, Northern China, and certain areas of Korea. You can find it as an ornamental plant throughout various parts of the world. It’s a woody vine with pink, oval-shaped flowers, and bright red berries.

In ancient China, it was used by royalty to help prevent aging and improve reproduction. Russian pilots used it to help them tolerate low-oxygen levels when flying at high altitudes in the 1940s.

Schisandra berries have also been used traditionally in Russia by hunters to help combat fatigue. The berries have high levels of antioxidants and is considered one of the most highly protective of all medicinal plants. The berries are often incorporated into a variety of herbal formulas.

A plethora of studies on animals has shown schisandra to provide stress-protective effects against a wide range of stressors.



Holy Basil


This variety of basil, also known as Tulsi different but related to the common culinary basil, grows primarily in India and South East Asia.

Ayurveda praises Holy Basil as an elixir of life and is often used as an essential oil for cosmetic purposes, or drunk in a tea or eaten as a powder.

Holy Basil balances the body and reduces stress, and studies have found that it is a strong antioxidant and may help to combat cancer.

You can grow your own holy basil quite easily, in your garden or windowsill to use the fresh leaves in your cooking or to make a tea. Dried tulsi (holy basil) tea bags are also commonly found in markets and health food stores.


Product Finder:



Licorice Root


The name licorice is from the Greek, meaning ‘sweet root’ and is well known as a traditional European candy, but it has been used in herbal medicine long before it was a flavoring agent.

In Chinese medicine, licorice is an important ingredient and used widely to harmonize formulas and carry the medicinal properties to the twelve meridians of the body. In Ayurveda, licorice is used for rejuvenation. Modern medicine has found the plant to be anti-viral and anti-inflammatory, and a strong adaptogen.


This spice is available in extract form and helps to increase the DHEA in your body. (6) Licorice root is associated with some side effects and may sometimes be avoided by taking DGL licorice. (7)


Pregnant women and those with heart, liver or kidney problems should avoid licorice root. Don’t take it for more than four weeks at a time. (8)



Fish Oil (EPA/DHA) and Algal Oil


There are a large number of benefits of supplementing with fish oil.

For people on vegan or other plant-based diets, use  algal oil.


Example: Healthy Fats Co. Algal DHA Oil


Several of these include counteracting a number of adrenal fatigue-related symptoms and complications, such as diabetes, mental dysfunction, arthritis, immune system function, skin issues, weight gain and anxiety/depression.





For some time, magnesium has been understood as one of the necessary nutrients for fighting adrenal insufficiency. (9)

While the mechanisms of this aren’t fully understood, you may benefit from supplementing with magnesium if you are suffering from adrenal fatigue.



B-Complex Vitamins


Research has found that vitamin B12 deficiency may be associated with stress on the adrenal cortex in some animals. (10)

Vitamin B5 is another commonly deficient vitamin in people with adrenal stress. Especially if you’re reducing or eliminating meat from your diet in order to fight adrenal fatigue, it may serve you well to take a high-quality B-complex vitamin supplement.



Vitamin C


Known as a “stress-busting” nutrient, vitamin C has been found to minimize the effects of stress on people as well as reduce the time necessary to bounce back from stressful events. (11)



Vitamin D


In addition to maintaining homeostasis between magnesium and phosphorus in the body and supporting strong bones, vitamin D has also more recently been seen to have impact on other conditions, including adrenal dysfunction and disease. (12)





At least one animal study has found that selenium deficiency can negatively impact adrenal function. (13)



Lavender Oil


Human and animal studies show that lavender essential oil has a calming effect that can reduce stress. (14) Research also suggests that it may lower high cortisol levels when inhaled. (15, 16)



Rosemary Oil


Inhaling rosemary essential oil (along with lavender) can help to decrease cortisol concentrations and reduce oxidative stress on cells. (17)

Use whole-food-based supplements from reputable companies which use only 100 percent, therapeutic grade, USDA Certified Organic essential oils. Make sure you trust what you’re purchasing.



Final Thoughts


Adrenal Fatigue is a frustrating syndrome. 

In addition to dealing with the sometimes debilitating symptoms, the Endocrinology Society and all the medical specialties do not recognize this condition. The Endocrinologists are categorical: “no scientific proof exists to support adrenal fatigue as a true medical condition.”

But that doesn’t change the way you feel, and you know when something is not right.

Because of the controversial nature of this condition, you will need to be proactive with self care, and may need to seek out a naturopath who will help you treat adrenal fatigue with a combination of dietary advice and supplement recommendations, as well as any hormonal or other medications necessary.

In addition, some symptoms can be indicative of more serious conditions, so make sure to see your doctor if:

  • You experience one or a combination of adrenal fatigue symptoms for an extended period of time
  • Your symptoms have begun interfering with normal life relationships and/or activities, such as work, family time or school
  • Dietary and lifestyle judgments have not significantly improved your symptoms
  • Your sleeping patterns have shifted into insomnia and/or you are no longer able to get restful sleep, no matter how long you’re in bed
  • You experience hyperpigmentation, or patches of darker skin on your body
  • You are a woman who has ceased menstruating
  • You experience dizziness and/or overall weakness for multiple consecutive days with no explainable cause (such as flu, concussion or excessive exercise)
  • You are unsure of how or unable to study adrenal fatigue supplements to safely take them, or unsure of how to structure an adrenal fatigue diet


 I wish you a speedy recovery!


Other Sources:

  • U.S. National Library of Medicine
  • National Institutes of Health
  • Cochrane Library of Systematic Reviews of Studies



Thanks for visiting and reading …

I hope this article provided you some useful information on pregnenolone as a treatment for Adrenal Fatigue Syndrome.

Your comments are most welcome!



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