Pregnenolone: The “Mother” Hormone For Better Brain Health
By Jay Campbell
September 16th, 2021
I AM bringing back the “testosterone bro” to talk about Pregnenolone, one of the most vital hormones you should be tracking if you’re on testosterone optimization therapy (TOT).
It plays a critical role in your overall cognitive health, and any physician specializing in male hormone management knows it MUST be at the right level for the patient.
But as with any concomitant medication, not everyone should be using it.
Some people will need to supplement with it, and other people will do well with their body’s natural levels.
So when should YOU be using pregnenolone while on TOT?
This article will answer that question and dispel all the myths behind Pregnenolone use once and for all.
MAJOR shoutout to my good friend Dave Lee for helping me write this article.
He is one of the foremost hormone health optimization coaches in the world when it comes to helping men get more out of their therapeutic testosterone regimens via smart blood work and finding the right physician.
Most of what is featured here can be found in his two lecture videos below:
What Is Pregnenolone?
Many people refer to Pregnenolone as the “mother” hormone or the “master” hormone for one specific reason:
If you look at the natural synthesis of pregnenolone in your body, it is THE direct precursor for several important steroids such as progesterone, cortisol, cortisone, aldosterone, DHEA (de-hydro-epi-androsterone), testosterone, dihydrotestosterone, estradiol, estrone, and allopregnanolone.
If the above diagram is too much to handle at once, here is a simplified version taken from the Testosterone Optimization Therapy Bible:
It is synthesized from cholesterol in the mitochondria via the CYP11A1 enzyme (a rate-limiting reaction) and can be found in multiple parts of the body:
“Pregnenolone (PREG) is the main steroid synthesized from cholesterol in mammals and invertebrates. PREG has three main sources of synthesis, the gonads, adrenal glands and brain and is submitted to various metabolizing pathways which are modulated depending on various factors including species, steroidogenic tissues and steroidogenic enzymes.”
“…In humans, PREG was first used in clinical practice as an anti-inflammatory agent in the 1940s , and placebo-controlled human trials with PREG demonstrated significant improvements in mood, general well-being, psychomotor performance and learning in normal controls tested under stressful conditions, with minimal side effects. More recently, PREG treatments have shown beneficial effects in depression- and psychosis-related disorders, such as shizophrenia.”
(BTW, the review linked above is an excellent summary of pregnenolone’s multiple uses for treating various mental health disorders)
Pregnenolone is metabolized via steroid sulfotransferase into its primary metabolite “pregnenolone sulfate”, which can be converted back into pregnenolone via steroid sulfatase.
Funny enough, pregnenolone has a half-life of around 40 minutes while pregnenolone sulfate has a 7-22 hour half-life.
How Does Pregnenolone Work In The Human Body?
Pregnenolone’s primary mechanism of action involves its behavior as an active neurosteroid:
“Sulfated steroids like pregnenolone sulfate and dehydroepiandrosterone sulfate can produce profound effects on behavior. PS [pregnenolone sulfate] as an abundant neurosteroid enhances learning, and antagonizes the impairment of learning and memory produced by ethanol and scopolamine. PS may play a role in cognition and have been reported as negative modulators of the GABAA-receptor based on electrophysiological studies and GABA-mediated 36Cl− uptake by rat brain synaptosomes “
The inhibition of GABA, a neurotransmitter associated with calmness, would you make you think that pregnenolone is an excitatory neurosteroid (i.e. a stimulant that increases brain activity).
Yet pregnenolone is associated with a relaxing effect, which can likely be explained by its subsequent conversion to allopregnanolone (the conversion schematic can be found here), along with the inhibition of the stress hormone cortisol.
Hence why pregnenolone is believed to be the “Valium” of the human body, and why elevated levels of stress and anxiety may be linked to a pregnenolone deficiency.
And why it also turns out that dosing pregnenolone properly and optimizing its levels in your body follows a “U-shaped” curve:
Since pregnenolone tunes the sensitivity of the receptor that binds to GABA (thus giving the receptor more/less activity), we have to be very careful of how it’s used in humans.
Too much pregnenolone means GABA will be running too low, while too little means GABA will be running too high — a “negative response” at either extreme.
As you saw in the diagrams in the previous section, pregnenolone sits at the pinnacle of a hormonal cascade which can influence the quality of aging and neuronal functioning… thus playing an important role in alertness, cognition, memory, and mood (more on that later).
In fact, the most obvious sign of deficient pregnenolone levels is a loss of memory (or a decrease in cognition).
Sadly, pregnenolone levels decline with age, “about 60% less at age 75 than at age 35” (Source).
Dave goes as far as to list additional symptoms closely associated with low pregnenolone levels:
- Inability to tolerate optimal doses of therapeutic testosterone (more info later in this article)
- Constant feeling of “fight or flight” (likely due to an overactivated amygdala)
- Inability to relax and “switch off”
- Feeling overwhelmed by objectively easy tasks, as if the brain is not working properly
- Low threshold to stress
- Low levels of joy or satisfaction
But is there enough evidence to support pregnenolone’s role in cognition?
Pregnenolone’s Mental Health Benefits
Despite pregnenolone being well-known in medicine and having been used since the early 1900’s, there’s not an awful lot of human studies.
But we have more than enough compiled evidence to ascertain its effects on mental health.
The best summary of all these effects can be found in a well-written article by SelfHacked, yet it’s prudent I summarize some of them here.
First off, lower pregnenolone levels can act as a useful biomarker in diagnosing age-associated cognitive decline:
“Strong evidence from animal studies suggests that neurosteroid levels, including pregnenolone, diminish with advancing age.
As pregnenolone is the parent compound of other vital neurosteroids such as dehydroepiandrosterone (DHEA), declining levels of pregnenolone could leave brain cells increasingly vulnerable to damage, such as overstimulation by neurotransmitters like glutamate.
In fact, scientists have proposed that levels of neurosteroids such as pregnenolone could serve as biological “markers” of cognitive aging in laboratory animals, allowing us to examine the age-related impact of each neurosteroid on learning and memory”
Pregnenolone is also shown to have anti neuroinflammatory effects and has great promise for diseases such as Alzheimer’s and Parkinson’s:
“Scientific researches demonstrated that pregnenolone can be fundamental to reduce the production of beta-amyloid proteins. In fact, it has been found out that the first physiological reaction central nervous system carries out against these toxic structures is to raise the quantity of the neurosteroid in the brain. Such a reaction demonstrates that pregnenolone is involved in the neurodegeneration of these cerebral anomalies.”
“The way pregnenolone positively works on Parkinson’s symptoms is not clear yet, although we can advance some hypothesis about it: the neurosteroid could act on the pathology through its neuroprotective and neurogenic properties besides the influence it has on sigma 1 receptors, which are responsible for the regulation of dopamine release. As a consequence, it is clear that pregnenolone could not only relieve the symptoms, but also slow the disease’s advancement.”
And based on what we know, pregnenolone may be able to improve focus and concentration:
“… [Pregnenolone] decreases the activity of the calming neurotransmitter GABA, and stimulates the NMDA receptors. The NMDA receptor deals with two primary neurotransmitters: glutamate, the neurotransmitter that stimulates it, and glycine, the neurotransmitter that calms it down.
Stimulation causes a calcium channel to open, while calming it down closes the calcium channel. Calcium in this case is carrying an electrical charge… so think of it like a bolt of electricity. Pregnenolone will also encourage release of dopamine, the neurotransmitter involved in focus and often inhibited in times of high stress.”
Pregnenolone’s ability to improve memory is scientifically uncertain, but Dave has anecdotally seen vast improvements:
“Preliminary research shows that pregnenolone may help protect against aging-related memory impairment. In a 2001 report published in Brain Research Reviews, for instance, investigators analyzed the available studies on steroid hormones and their effects on learning and memory in the aging brain.
But while research in animals demonstrated that pregnenolone may enhance memory, the report’s authors note that human-based studies on pregnenolone and memory have yielded mixed results.”
Additionally, we have numerous animal studies demonstrating pregnenolone’s effects on lowering neuron toxicity, enhancing neuron survival, and increasing the growth of new neurons:
“PROG increases proliferation and induces maturation of rat immature oligodendrocytes.
PROG regulates the formation of myelin sheaths in regenerating axons of spinal cord motor neurons in Wobbler mouse.
PROG reduces myelin impairments in sciatic nerve of aged rats
PROG and Allo exert antiapoptotic and antigliotic effects after brain injury in rats”
Although pregnenolone may not be FDA-approved for anything related to health, some potential uses in humans include:
- Improving deep sleep quality
- Fixing depressive symptoms in bipolar patients
- Targeting negative symptoms in people with schizophrenia
In short: We have a neurohormone that’s very important for mental function, verbal acuity, memory, and overall cognitive function.
The Optimal Dose Of Pregnenolone For Enhanced Cognitive Function
When I first wrote about Pregnenolone in The TOT Bible, I admittedly gave a cookie-cutter recommendation for dosing pregnenolone:
“The typical dose of pregnenolone is between 30-60 mg per day, usually taken at night along with DHEA. The pills are meant to be taken on an empty stomach, or you can use a cream (i.e. transdermal application). Pregnenolone can be purchased over the counter (OTC) as a pill form (micronized slow release is the best for oral pills), or as a sublingual (under the tongue) treatment, in addition to transdermal applications.
There is also the option of adding hCG to your TOT to help keep your pregnenolone, progesterone, and DHEA levels consistent. hCG activates the enzyme that turns cholesterol into pregnenolone. This ensures that your body gets the pregnenolone it needs to produce all the other important hormones.”
I did not expand on why DHEA supplementation was necessary, but Nelson Vergel fills in the blanks:
“Aside from the natural decrease in pregnenolone that occurs as you age, research shows that higher doses of Testosterone Replacement Therapy (TRT) cause pregnenolone blood test levels to drop even further. This leads to a decrease in both DHEA and sex- hormone binding globulin (SHBG), two very important hormones for sexual health and libido. The decrease can be as high as 80 or 90%!
However, there is a simple solution: add HCG to your supplementation.
If you are considering undergoing TRT and are worried about your precursor hormone levels, adding HCG into the mix will help to keep your pregnenolone, progesterone, and DHEA levels consistent. HCG is a luteinizing hormone analog, and it activates the enzyme that turns cholesterol into pregnenolone. This ensures that your body gets the pregnenolone it needs to produce all the other important hormones.”
Restoring pregnenolone to optimal levels is critically important for overall hormonal health, especially for those undergoing TOT/HRT.
But Dave Lee’s newest research implies that the subject of deciding the best dose for both pregnenolone and DHEA is a bit more complicated.
First off, as I wrote in The TOT Bible, your genetic predisposition will be a direct determinant of how well you can tolerate both compounds.
“For example, a variation (rs6971) in the gene TSPO can influence internal production of pregnenolone (i.e. decrease production), meaning you may need to take a supplement to elevate pregnenolone levels to normal“
In other words, people with genetic polymorphisms in the sulfation pathway won’t have as much enzyme available to do the necessary conversions to the sulfated forms of both compounds… thus you will need lower split dosing to ensure optimal ratios between Pregnenolone and Pregnenolone sulfate, and DHEA and DHEA sulfate.
(Dave also recommends increasing cholesterol intake and sun exposure, along with intake of sulfur-containing foods to counteract this)
Second, pregnenolone and DHEA can have synergistic yet opposing effects: Pregnenolone is often sedating and DHEA is often energizing, but when used together the sedating effect can allow both to be taken in the evening.
Third, the condition you are treating will require different doses for both pregnenolone and DHEA:
- Brain injury / PTSD: 100-150 mg Pregnenolone and 25-50 mg of DHEA
- Age-related hormonal decline: 50-100 mg Pregnenolone and 10-25 mg DHEA
- Chronic pain management: as high as 200-500 mg Pregnenolone and 100-200 mg DHEA
In general, a higher ratio of Pregnenolone:DHEA will be more relaxing, while a higher ratio of DHEA:Pregnenolone will be more stimulating
Fourth, the optimal pregnenolone and DHEA doses vary unpredictably due to individuality.
Some individuals will require 5 mg of pregnenolone per day and others will require 200 mg due to factors such as body weight, testosterone dose, root cause of deficiency, etc.
If used individually, pregnenolone can be taken when feels best and DHEA should be taken in the morning (to better sync up with your circadian rhythm).
Fifth and finally, the route of administration entirely dictates how pregnenolone will be metabolized.
The optimal routes of administration are as follows: Sustained release micronized tablets/capsules, transdermal or sublingual.
You MUST use sustained release as an instant-release oral formulation of pregnenolone will be rapidly converted to progesterone via first-pass metabolism in the liver.
The first two dosing choices listed provide a slower release into the system that allows the body to convert pregnenolone to pregnenolone sulfate and avoid the first-pass liver metabolism.
Sublingual administration, on the other hand, is believed to increase pregnenolone levels in the brain due to greater access to the sulfotransferase system (similar to using scrotal testosterone cream to get better “access” to the enzymes we want to target).
The ONLY Situations Where You Should Be Using Pregnenolone
If you choose to only read one section of this article, make sure it’s this one as it is by far the most important.
Because the goal is NOT to have people blindly using pregnenolone… the goal is to get your levels tested, review all your symptoms, speak with a doctor experienced in managing the entire male endocrine system, start with a low dose of pregnenolone (as low as 1mg), and titrate up SLOWLY with regular bloodwork.
To start off, here’s a recap of what happens to your pregnenolone levels when you start using therapeutic testosterone:
“…when on testosterone optimization therapy (TOT), you will suppress the production of Luteinizing hormone (LH), which is critical for the conversion of cholesterol into pregnenolone and its metabolites.
LH stimulates steroidogenesis by up-regulating the rate limiting transport of cholesterol into the inner mitochondrial membrane.
LH increases the expression of the P450 cholesterol side-chain cleavage enzyme, which then catalyzes the conversion of cholesterol into pregnenolone”
From this, people will wrongly conclude that TOT shuts down the production of pregnenolone and DHEA throughout the entire body.
FALSE — production is shut down exclusively in the Leydig cells found in your testes, which is a natural consequence of the reduced demand for pregnenolone/DHEA when testosterone/estrogen are optimized (i.e. replaced via exogenous administration, and remember that testosterone is a subject of pregnenolone metabolism).
As Dave puts it:
“TOT shuts down CYP11A1 in the Leydig cells.
Pregnenolone is produced by the mitochondria throughout the body (the shut down is local and NOT systemic).
Therefore TOT will reduce pregnenolone slightly”
There is no literature that proves these hormones are depleted in other glands.
Second, your default assumption should NOT be to automatically use pregnenolone just because you have “low levels” or you are on some form of TOT.
But don’t automatically assume that you need to make the classic mistake of mindlessly chasing lab numbers… you need to have your pregnenolone deficiency diagnosed by SYMPTOMS in addition to low cortisol/pregnenolone/DHEA readings.
For instance, given that pregnenolone is directly derived from cholesterol, suboptimal cholesterol levels will lead to suboptimal pregnenolone levels (and can be fixed with something as simple as changing your dietary choices)
Furthermore, the requirements for pregnenolone, DHEA, and thyroid use while on TOT are highly individual and depend on the individual’s biochemistry and root cause of hypogonadism.
This is why the dosing recommendations given in the previous section were highly variable as there is no “universal” protocol for using pregnenolone (even though all individuals will likely benefit from supplementing both pregnenolone and DHEA as they age due to the decline of natural production).
Numerous factors can be responsible for the cause of low pregnenolone/DHEA levels:
- Chronic or intractable pain
- Head trauma
- Early anabolic steroid use
- Genetics (certain enzyme deficiencies will call for a higher dose)
- Bioavailability and quality of the form of pregnenolone being administered, as no form is 100% bioavailable (i.e. just because you take 50mg DHEA doesn’t mean your body is getting 50mg DHEA)
Which means if an individual is not feeling good and they have average DHEA/adrenal hormone levels, it’s critical to look elsewhere for the root cause of their problems.
After all, it’s entirely possible to over-dose pregnenolone and counteract the effects of TOT!
Finally, you need to ONLY be using pregnenolone alongside an experiential-based hormone optimization physician.
Dr. Rob Kominiarek tells all in the short video below:
(For the FULL episode from where this video clip was generated, go here)
Or as he mentioned in his contribution to The TOT Bible:
“If your pregnenolone is below those levels, speak to your doctor about potentially beginning a course of pregnenolone supplementation. If your levels are around that number, you may not need to take pregnenolone.
Dr. Rob Kominiarek specifically states that in his practice, supplementing with pregnenolone is purely dependant on symptoms of a deficiency (loss of memory, decrease in cognition, etc.) rather than just lab measurement numbers. He also tests a patient’s pregnenolone levels prior to starting TOT, 3 months after starting and also 12 months later.”
To sum up everything in brief bullet points:
- It is important (as with all forms of hormone supplements and medications) to assess whether there is a clinical need (i.e. a measured deficiency via lab work, and more importantly, the presence of SYMPTOMS) before one starts taking pregnenolone (Dr. Kominiarek very rarely uses it in his clinical practice)
- People who NEED pregnenolone are usually people suffering from brain injuries (head trauma can disrupt the cholesterol -> pregnenolone conversion), or people whose pregnenolone production is heavily impaired by the use of DHT inhibitors such as Finasteride
- Testing your pregnenolone levels is reliable when you are administering it exogenously (i.e. from outside the body): Test, don’t guess!
- Recommendations vary widely for the dose – start with 1mg, titrate up slowly, and stop when you reach the optimal amount.
- You WILL have negative side effects if your pregnenolone levels were already good to begin with) — too much isn’t better than not enough
Before I recommend Dave’s top 3 sources for buying pregnenolone, let me go over one final note…
The only thing you really have to worry about – assuming you follow all of the instructions – is having a history of seizures (pregnenolone and its metabolite pregnenolone sulfate have been associated with increased seizure activity).
There are known side effects of pregnenolone administration that include increased production of estrogen, but again, won’t happen if you use pregnenolone correctly and ONLY when needed.
The BEST Places To Buy Pregnenolone Online
Dave highly recommends the micronized/sustained release capsules because they yield the smoothest and best subjective response.
While you ideally want to get pregnenolone from a doctor’s prescription, there are over-the-counter sources from quality hormone manufacturers you can opt for.
It’s super-accessible and you can buy it from any country online in the world, but we don’t advise you to just pick it up from your local Walmart.
So here are Dave’s top 3 sources for getting the desired oral formulations of Pregnenolone…
- The best OTC brand is Nutricology
- The best affordable brand is Life Extension
- Failing the two above, your best bet is to go with PureForYou
Working With Someone Who KNOWS How To Use Pregnenolone
Obviously, I can’t conclude this article without an endorsement of Dave Lee and his coaching practice.
He’s done wonders for men around the world in optimizing every last hormone in their body, and pregnenolone is just one of many vital male hormones he is intimately familiar with.
Alternatively, doctors like Dr. Rob Kominiarek are well-versed in this subject and have successfully helped thousands of patients return to a better quality of life.
But if you read all the way to the end of this article, you now know more than 99% of endocrinologists about the topic of pregnenolone.
Go forth and use this information to live a fully optimized life!
And as always…