Pregnenolone for Men: What We Need to Know

[Nelson Vergel]

Pregnenolone for Men: An Insight into this Neurosteroid and Male Health​

Introduction​

Pregnenolone, a naturally occurring steroid in the human body, has recently become a focal point in medical research, particularly concerning its effects on male health. This article talks about different studies that look at the role of pregnenolone in things like brain function, hormone balance, and how it might be used to treat conditions like schizophrenia. By examining findings from a range of research papers, we aim to provide a comprehensive understanding of how pregnenolone impacts men's health.

The Neurosteroid Pregnenolone: A Primer​

You could almost say pregnenolone is the "father" of all hormones!
Your body produces hormones from cholesterol, the sterol lipid molecule synthesized in our liver. But your body has to go through a process in order to produce hormones like testosterone, estrogen, DHT, and so on. First, it has to turn the cholesterol into pregnenolone. From there, it can produce hormones like progesterone (which is where cortisol comes from) and DHEA (which is needed for the production of testosterone).


But that first step (turning cholesterol into pregnenolone) is the most important step. Pregnenolone is essentially the precursor to these other hormones, as you'll see in the chart below:



In a young adult male, pregnenolone levels are at their peak. However, as you age, the levels of this precursor hormone drop, until, at the age of 75, our bodies produce just 40% of the pregnenolone they need. That's a severe drop in the precursor hormone, which leads to a drop in all the hormones resulting from pregnenolone.

Before diving into specific studies, it's crucial to understand what pregnenolone is and its basic functions. Pregnenolone, often referred to as a neurosteroid, is a precursor to various other steroids, including testosterone. It is synthesized in the adrenal glands, brain, and gonads. This neurosteroid plays a vital role in synaptic plasticity, cognitive function, and mood regulation.

Pregnenolone Supplementation: Routes and Doses​

Pregnenolone can be administered orally, subcutaneously, intravenously, intranasally, and topically or transdermally. Oral pregnenolone has a high metabolism and low bioavailability. It is lipophilic and readily crosses the blood-brain barrier.

There is very limited data on the pharmacokinetics of exogenous pregnenolone. When taken by mouth, pregnenolone is broken down more quickly by allopregnanolone than by other hormones made from pregnenolone substrates, like cortisol or DHEA. One study observed that three hours after oral consumption of a single dose of 400mg of pregnenolone, pregnenolone serum levels increased by approximately 60%. Two hours after this dose, allopregnanolone serum levels tripled. An earlier study showed that a single oral dose of 175mg of pregnenolone approximately doubled pregnenolone serum levels over the course of four to eight hours.

One study by Marx et al. (2009) observed the effects of exogenous pregnenolone on patients diagnosed with schizophrenia or schizoaffective disorder. Participants were given eight weeks of oral pregnenolone with an escalating fixed-dose approach, where patients took 500mg per day for the last four weeks. Serum levels of pregnenolone and certain downstream metabolites were measured. When pregnenolone was taken by mouth, serum levels of pregnenolone four times higher, pregnenolone sulfate three times higher, and allopregnanolone five times higher. Also, taking oral pregnenolone increased the levels of progesterone in the blood by more than four times and the levels of DHEAS by about sixteen percent. In this study, exogenous pregnenolone did not increase serum levels of testosterone, free testosterone, cortisol, DHEA, estradiol, or androstenedione.

Pregnenolone and Allopregnanolone in Anxiety:​

Pregnenolone, a vital hormone in the human body, serves as the foundational precursor for the synthesis of allopregnanolone. This process is crucial because allopregnanolone plays a significant role in regulating mood and emotional states. Specifically, increased levels of allopregnanolone have been linked to a reduction in anxiety symptoms. This anxiolytic effect demonstrates the hormone's influence on mental well-being. Conversely, the blockade or inhibition of allopregnanolone can lead to negative impacts on both social and affective functioning. This means that if the production or activity of allopregnanolone is slowed down, it could make it harder to interact with others and control your emotions. This shows how important the hormone is for mental health and social well-being.

Have you ever wondered how your brain manages emotions, especially during times of stress or anxiety? This question has long piqued the interest of scientists. A recent study delves into the role of a neurosteroid called allopregnanolone in emotional regulation. This substance is known for its calming effects and has been linked to anxiety reduction. However, the way it influences our brain's emotional control circuits has remained largely a mystery until now.

To understand allopregnanolone's role better, researchers conducted an innovative experiment. They administered 400 mg of pregnenolone (a precursor to allopregnanolone) to 16 participants and a placebo to another 15. The participants then underwent a type of brain imaging called 3T fMRI while performing a task called the Shifted-Attention Emotion Appraisal Task (SEAT). This task is designed to assess emotional processing and regulation.

The results were quite revealing. Compared to the placebo group, those who received allopregnanolone showed reduced activity in two brain regions: the amygdala and the insula. These areas are often associated with generating negative emotions like fear and anxiety.

Allopregnanolone was found to make the dorsal medial prefrontal cortex work harder during the part of the task that involved judging emotions. This is a part of the brain that is linked to controlling emotions. Moreover, it enhanced the connection between the amygdala and this region. This change correlated with lower levels of self-reported anxiety among participants.

Pregnenolone in Schizophrenia Treatment​

Several studies have investigated the potential of pregnenolone in treating schizophrenia, a mental disorder characterized by cognitive and mood disturbances. For instance, Marx et al. (2014) conducted a randomized controlled trial to assess the efficacy of pregnenolone in schizophrenia. Their findings suggested some improvement in cognitive functions and symptom alleviation.

Similarly, Marx et al. (2009) also explored the effects of pregnenolone on cognitive and negative symptoms in schizophrenia. This proof-of-concept trial reinforced the potential benefits of pregnenolone in enhancing cognitive functions in schizophrenia patients.

Ritsner (2010) provides a broader perspective on pregnenolone, dehydroepiandrosterone (DHEA), and their alterations in schizophrenia. This study tells us a lot about the changes in hormones that happen in men with schizophrenia, which makes the possible therapeutic role of pregnenolone even more clear.

Cognitive and Mood Enhancements​

Beyond schizophrenia, pregnenolone's role in general cognitive and mood improvements has been a subject of interest. Osuji et al. (2010) studied the effects of pregnenolone on cognition and mood in dual-diagnosis patients. Their research hinted at the potential of pregnenolone in improving cognitive function and mood, although the scope was limited to a specific patient group.

Hormonal Effects in Men​

The hormonal effects of pregnenolone, especially concerning testosterone levels, have been studied extensively. In 2023, Bracci et al. looked at changes in pregnenolone and testosterone levels in male shift workers. This study showed how work schedules might affect hormonal balance. Their findings highlighted the significant role of pregnenolone in maintaining hormonal equilibrium.

Pregnenolone in Age-Related Hormonal Changes​

Morley (2013) has looked into the role of pregnenolone in age-related hormonal changes, particularly with regard to rejuvenation and vitality. His overview of hormone treatments used for rejuvenation touches upon the significance of pregnenolone in maintaining hormonal balance as men age.

Pregnenolone's Role in Synaptic Plasticity​

Synaptic plasticity is a term used in neuroscience, the study of the brain and nervous system. To understand it, think of your brain as a network of roads, where each road is a connection between brain cells (neurons). These roads are called synapses.

Imagine how these roads can change. Some can become wider or more used, making the travel (or communication) between brain cells faster and stronger. Others can become less used or even disappear. This changing nature of the roads (synapses) is what we call synaptic plasticity.

This concept is like learning and memory in the brain. When you learn something new or remember something, the roads in your brain adjust. Some connections become stronger because you use them more (like practicing a skill), and others weaken because you use them less.

So, synaptic plasticity is essentially the brain's ability to rewire itself based on experiences, learning, and memory. It's why we can learn new things and remember them. This flexibility is crucial for our brain's growth and adaptation throughout our lives.

Smith et al. (2014) provide a thorough examination of the part pregnenolone plays in synaptic plasticity. Their research underscores the role of neurosteroid in modulating synaptic plasticity, which has implications for cognitive functions and mental health.

One important discovery by Dr. Smith’s team was that pregnenolone helps brain cells communicate, especially in ways that are important for learning and remembering things. This communication happens through something called the N-methyl-D-aspartate receptor (NMDAR), which is like a tiny receiver on brain cells that helps them talk to each other. These scientists found that pregnenolone can move these NMDARs to where they're needed on the brain cell surface. It does this with the help of calcium ions (tiny particles) and something called G-protein-coupled receptors. Also, pregnenolone can increase the levels of calcium inside brain cells, which is really important for strengthening brain cell connections. This strengthening is what helps us learn and remember things.

Testosterone Replacement Therapy and Anabolics Decrease Upstream Hormones like Pregnenolone​

To comprehend pregnenolone's impact fully, it's also essential to understand its relationship with testosterone and other steroid precursors. Ruokonen et al. (1985) explored the response of serum testosterone and its precursor steroids to anabolic steroids and testosterone administration, providing a foundational understanding of how pregnenolone interacts with other hormones.

The influence of high doses of testosterone and anabolic steroids on testicular endocrine function and on circulating steroid-binding proteins, sex hormone-binding globulin (SHBG) and cortisol-binding globulin (CBG), was investigated in power athletes for 26 weeks of steroid self-administration and for the following 16 weeks after drug withdrawal. Serum testosterone and androstenedione concentrations increased (P less than 0.05) but pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 5-androstene-3 beta, 17 beta-diol, progesterone, and 17-hydroxyprogesterone concentrations strongly decreased (P less than 0.001) during steroid administration. Serum pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone sulfate concentrations followed the changes of the corresponding unconjugated steroids, but 5-androstene-3 beta, 17 beta-diol, and testosterone sulfate concentrations remained unchanged during the follow-up time.

During drug administration, SHBG concentrations decreased by about 80–90% and remained low even for the 16 weeks following steroid withdrawal. Steroid administration had no influence on serum CBG concentrations. In conclusion, self-administration of testosterone and anabolic steroids soon led to impairment of testicular endocrine function, which was characterized by low concentrations of testosterone precursors, high ratios of testosterone to its precursor steroids, and low SHBG concentrations. Decreased concentrations of SHBG and testicular steroids were still partly evident during the 16 weeks after drug withdrawal. The depressed circulating levels of dehydroepiandrosterone and its sulfate may indicate that the androgenic-anabolic steroids also suppress adrenal androgen production.

Drawbacks of Pregnenolone Supplementation​

Now, as with any hormone, there are a number of drawbacks of pregnenolone supplementation. Not everyone will experience side effects, but most users report one or more of the following:

• Bloating -- Many pregnenolone users have reported feeling bloated and puffy with regular use, even when taking the hormone in tandem with DHEA or other steroid hormones. This may be due to the fact that pregnenolone increases the production of ALL sex hormones, including estradiol (the precursor to estrogen). An increase in estrogen can increase water retention, leading to bloating.
• High Estrogen Levels -- As mentioned above, pregnenolone is turned into a lot of different sex hormones, including various forms of estradiol. This increase in estradiol can cause your estrogen levels to rise.
• Strange Dreams -- A number of people taking pregnenolone have reported vivid, strange dreams after taking the supplement. While pregnenolone can help to reduce anxiety and stress (as we saw above), it has been known to cause your brain to be over-active when you sleep and may lead to odd dreams.
• Other Side Effects -- According to WebMD "There isn't enough information to know if pregnenolone is safe when taken by mouth." However, it has been known to cause effects similar to those resulting from other steroid hormones: arrhythmia, hair loss, facial hair growth, headaches, negative mood changes, acne, anger, anxiety, irritability, and insomnia. For those with hormone-sensitive conditions (like breast, ovarian, or uterine cancer, or endometriosis), the hormone may increase health problems thanks to the fact that pregnenolone increases the production of estrogen.
• However, the truth is that these drawbacks are really fairly minimal. For the most part, pregnenolone is a fairly safe option with limited side effects. However, it's important that you understand what you're getting into when taking pregnenolone.

How Much Pregnenolone Do You Need?​

If you are considering taking it to increase natural hormone production, it's vital that you know HOW MUCH to take. The last thing you want is to overdo it and end up suffering negative side effects!

According to the Quest Diagnostics Manual, normal circulating levels of pregnenolone are as follows:

• Men: 10 to 200 ng/dL
• Women: 10 to 230 ng/dL
• Children: 10 to 48 ng/dL
• Adolescent boys: 10 to 50 ng/dL
• Adolescent girls: 15 to 84 ng/dL

Mean levels of pregnenolone have been found not to significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively)

The typical dose of pregnenolone is between 50 and 200 mg per day, usually taken first thing in the morning. The pills are meant to be taken on an empty stomach, or you can use a cream (transdermal application).

However, you may want to consult with your endocrinologist before taking any pregnenolone. They may recommend a higher or lower dosage according to your pregnenolone levels, or they may counsel you against it. It's essential that you get a recommendation from a medical professional before you take any sort of supplement, especially hormones like pregnenolone.


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Conclusion​

The body of research on pregnenolone illuminates its multifaceted role in men's health, particularly concerning cognitive function, mood regulation, and hormonal balance. While it shows promise in treating conditions like schizophrenia and improving cognitive and mood functions, more research is necessary to fully understand its therapeutic potential and long-term effects.

References​

1. Marx, Christine E. et al. “Proof-of-Concept Randomized Controlled Trial of Pregnenolone in Schizophrenia.” Psychopharmacology 231.17 (2014): 3647–3662.
2. Bracci, Massimo et al. “Alterations in Pregnenolone and Testosterone Levels in Male Shift Workers.” International journal of environmental research and public health 20.4 (2023): 3195-.
3. MARX, Christine E et al. “Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia.” Neuropsychopharmacology (New York, N.Y.) 34.8 (2009): 1885–1903.
4. Osuji, I. Julian et al. “Pregnenolone for Cognition and Mood in Dual Diagnosis Patients.” Psychiatry research 178.2 (2010): 309–312.
5. Ritsner, Michael S. “Pregnenolone, Dehydroepiandrosterone, and Schizophrenia: Alterations and Clinical Trials.” CNS neuroscience & therapeutics 16.1 (2010): 32–44.
6. Morley, John E. “Scientific Overview of Hormone Treatment Used for Rejuvenation.” Fertility and sterility 99.7 (2013): 1807–1813.
7. Smith, Conor C., Terrell T. Gibbs, and David H. Farb. “Pregnenolone Sulfate as a Modulator of Synaptic Plasticity.” Psychopharmacology 231.17 (2014): 3537–3556.
8. Ruokonen, A. et al. “Response of Serum Testosterone and Its Precursor Steroids, SHBG and CBG to Anabolic Steroid and Testosterone Self-Administration in Man.” Journal of steroid biochemistry 23.1 (1985): 33–38.
9. The Quest Diagnostics Manual: Endocrinology: Test Selection and Interpretation

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[Jerajera]

@Nelson Vergel, do you know whether Empower's Pregnenolone (and DHEA) capsules are micronized? I always assumed they were but I don't see any mention of that on their website.

Also do you have any idea about whether the Pregnenolone used in those research papers is micronized? I don't think I've ever seen mention of that, but I can't imaging it wouldn't significantly impact dosage based on the increased bioavailability.