Pregnenolone in Men: Help determining proper dosage and frequency

Hi all,
I've been experimenting with pregnenolone for over a year now, with varied success. I seem to get benefits at 100mg (such as higher libido, more pronounced nighttime erections and better sleep); however, I don't get these results consistently. If I try to continue 100mg daily, the effects start waning by the second day (my theory for this is possibly progesterone elevating too high). I've also tried lowering the dose to 10mg, 25mg and 50mg; however, oddly enough, I only seem to get the benefits at 100mg. Extended use at the other doses eventually builds up and produces only negative effects. Anyway, I was wondering if anybody could clarify the half-life of pregnenolone, its sulfate derivative, and its conversion to progesterone and could offer any insight on dosing frequency.

By the way, I've experimented with just progesterone, but the benefits are less pronounced, and I become more susceptible to the negative effects.

(sorry for the long-winded ramble)

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Pregnenolone Supplementation in Men: Dosage, Effects, and Considerations​

This briefing document summarizes key themes and important facts regarding pregnenolone supplementation, primarily for men, drawing from discussions and articles within the "Excel Male TRT Forum." The information covers optimal dosing strategies, the hormone's metabolism, its potential benefits and side effects, and interactions with other hormones like progesterone and DHEA.

1. Pregnenolone Metabolism and Half-Life​

Pregnenolone is a precursor hormone, meaning it can convert into various other downstream hormones including progesterone, DHEA, allopregnanolone, and even cortisol. This metabolic versatility explains its varied effects.

• Half-Life: Pregnenolone itself has a relatively short half-life of 3 to 4 hours. However, it is converted into pregnenolone sulfate, which has a longer half-life of 10–12 hours. This extended presence of its derivative allows for a more sustained effect in the body. (Nelson Vergel, Jul 27, 2021, #2)
• Conversion Pathways: A significant amount of pregnenolone is broken down into progesterone. Progesterone can then be further converted into cortisol or allopregnanolone, a potent GABAergic neurosteroid. (Nelson Vergel, Jul 27, 2021, #2)
• Liver Metabolism: Oral pregnenolone has high metabolism and low bioavailability, with significant conversion into other steroids occurring in the liver. (JA Battle, Jul 27, 2021, #4)

2. Dosing Strategies and Effects​

Individuals respond differently to pregnenolone, with optimal dosing varying. The goal is often to maximize benefits while mitigating potential negative side effects, primarily due to progesterone accumulation.

• Individualized Response: The original poster, Sozzing, found benefits only at 100mg (higher libido, pronounced nighttime erections, better sleep), while lower doses (10mg, 25mg, 50mg) eventually led to negative effects. However, 100mg daily also saw effects waning by the second day, theorized to be due to elevated progesterone. (Sozzing, Jul 26, 2021, #1)
• Progesterone Accumulation & Receptor Downregulation: High doses can lead to progesterone build-up, causing declining returns or negative consequences such as "tiredness, brain fog, mood swings." Strong doses might also "overstimulate neurosteroid receptors, hence lowering sensitivity over time." (Nelson Vergel, Jul 27, 2021, #2)
• Recommended Dosing Techniques to Preserve Results: Pulsed Dosing: "Every Other Day or 2-3x Weekly pulsed dosing may help to prevent too high progesterone levels while still preserving the advantages at 100mg." (Nelson Vergel, Jul 27, 2021, #2)
• Alternative Administration: "Sublingual or transdermal" methods avoid first-pass liver metabolism, potentially yielding "a more constant and predictable impact." (Nelson Vergel, Jul 27, 2021, #2)
• Split Dosing: Breaking a large dose (e.g., 100mg) into "3x daily" smaller amounts may lead to "a more favorable ratio between pregnenolone sulfate, progesterone, and dhea." (JA Battle, Jul 27, 2021, #4)
• Morning Low Dose with Occasional Higher Dose: "Try 10–25 mg daily then, once or twice a week, 100 mg." (Nelson Vergel, Jul 27, 2021, #2)
• Typical Endogenous Production: An adult "roughly makes around 30mg per day" of pregnenolone. (JA Battle, Jul 27, 2021, #4)
• Observed Benefits (Nelson Vergel): Taking 100mg twice daily (total 200mg/day) led to "deeper sleep and more fluidity in my speech." (Nelson Vergel, Jul 31, 2021, #12) His pregnenolone levels increased from "almost undetectable to 95 ng/dL" on 100mg/day, with a "normal" range for men being 10-200 ng/dL. (Nelson Vergel, Jul 31, 2021, #12)
• Study Doses: Some studies have used significantly higher doses, such as 50mg twice daily ramping up to 250mg twice daily for depression in menopausal/perimenopausal women and up to 500mg per day for bipolar depression. One study even administered 400mg per day. (Nelson Vergel, Jul 31, 2021, #10, #11, #13)

3. Interaction with Other Hormones and Conditions​

Pregnenolone's effects are intertwined with other hormone levels and can be influenced by exogenous hormone therapies like TRT.

• Progesterone: Simply taking progesterone is "not as effective" as pregnenolone, as pregnenolone supports multiple metabolic routes, not just progesterone production. Direct progesterone bypasses the "upstream neurosteroid balancing," potentially causing imbalances. (Nelson Vergel, Jul 27, 2021, #2)
• DHEA: Combining pregnenolone with 10–25 mg DHEA might help "offset the slow down caused by too much or low progesterone" because they share metabolic pathways. (Nelson Vergel, Jul 27, 2021, #2) However, Nelson Vergel personally does not take DHEA, stating "TRT has very little effect on DHEA and my levels are usually mid range. The data on DHEA and mood is all over the place. Not a strong believer." (Nelson Vergel, Jul 31, 2021, #16)
• TRT and LH Hormone: For individuals on Testosterone Replacement Therapy (TRT), the absence of LH hormone can affect pregnenolone conversion. "Pregnenolone taken in one large dose will convert more heavily to progesterone and pregnenolone sulfate." This is "not reliable especially while on trt" because "LH is needed to ensure proper conversion of pregnenolone." hCG might spur conversion but in different ratios than natural pulsatile LH. (JA Battle, Jul 27, 2021, #4)
• Estrogen (E2): Pregnenolone is "so far up in the cascade" that Nelson Vergel has "not seen any increase in E2" in his experience. (Nelson Vergel, Aug 8, 2021, #20)
• NMDA Receptors: High doses, especially while on TRT, can lead to increased pregnenolone sulfate, which "agonizes nmda receptors." The negative symptoms experienced by Sozzing were similar to his experiences with glycine, which is also involved with NMDA receptors. (JA Battle, Jul 27, 2021, #4; Sozzing, Jul 28, 2021, #6)
• Allopregnanolone and Emotion Regulation: Pregnenolone administration leads to elevated allopregnanolone, which is associated with "reduced activity in regions linked to the generation of negative emotion," "increased activity in regions linked to regulatory processes," and "enhancement of functional connectivity" in the brain. This can lead to "less self-reported anxiety." Allopregnanolone is a "potent allosteric modulator of the GABA(A) receptor with anxiolytic properties." (Nelson Vergel, Jul 31, 2021, #13, quoting a study)

4. Supporting Compounds​

To manage potential side effects, particularly those related to progesterone accumulation and GABAergic effects:

• "Increasing your consumption of magnesium, taurine, or ashwagandha might help control GABA-related side effects if progesterone accumulation is causing unpleasant consequences." (Nelson Vergel, Jul 27, 2021, #2)

5. Administration and Testing​

• Administration Routes: Pregnenolone can be taken orally, subcutaneously, intravenously, intranasally, and topically/transdermally. Oral administration, however, has high metabolism and low bioavailability. (Nelson Vergel, Jul 27, 2021, #2, quoting "Pregnenolone and Progesterone for Men: Pharmacokinetics and Studies")
• Testing: Blood tests for pregnenolone and progesterone are available to monitor levels and guide dosing adjustments. (Nelson Vergel, Jul 27, 2021, #2, provides links to discounted labs)

In conclusion, pregnenolone supplementation is a complex area requiring careful consideration of dosage, frequency, and individual metabolic responses. While it offers potential benefits for libido, sleep, and mood due to its role as a precursor to various neurosteroids, managing its conversion, particularly to progesterone, is crucial to avoid adverse effects. Consulting with healthcare professionals and monitoring hormone levels are essential for safe and effective use.

 

Hello there,

Your experience with pregnenolone is really fascinating, and your hypothesis on the accumulation of progesterone is most likely accurate. Because pregnenolone metabolism produces downstream hormones including allopregnanolone, DHEA, even cortisol, its effects can be quite customized.

Half-life and metabolism of pregnenolone
Although its half-life is only 3 to 4 hours, pregnenolone itself can last longer in the body since it is converted into pregnenolone sulfate, which has a half-life closer to 10–12 hours.
A good amount is broken down into progesterone, which can either be further converted into cortisol (which can have either stimulating or suppressing effects, depending on levels) or allopregnanolone, a strong GABAergic neurosteroid.

Why the 100mg benefits differ?
Builder of Progesterone: As you pointed out, the conversion of pregnenolone to progesterone can build over time and cause declining returns or even negative consequences (e.g., tiredness, brain fog, mood swings).

Downregulation of Receptor: Strong doses could overstimulate neurosteroid receptors, hence lowering sensitivity over time. This would help to explain why you first get benefits but not always.
Cortisol Influence: Your body may vary in benefits if it drives more pregnenolone toward cortisol synthesis, therefore affecting energy and mood.

Dosing Techniques to Preserve Results

Consider these options as you react best to 100mg but observe declining results on consecutive days:

Every Other Day or 2-3x Weekly pulsed dosing may help to prevent too high progesterone levels while still preserving the advantages at 100mg.

These administration techniques—sublingual or transdermal—avoid first-pass liver metabolism, therefore perhaps producing a more constant and predictable impact.

Combining DHEA with pregnenolone will help as they share metabolic pathways. Some people find that adding 10–25 mg DHEA helps offset the slow down caused by too much or low progesterone.

Morning Low Dose; Higher Dose Sometimes For a boost, try 10–25 mg daily then, once or twice a week, 100 mg.

Increasing your consumption of magnesium, taurine, or ashwagandha might help control GABA-related side effects if progesterone accumulation is causing unpleasant consequences.

Why Is Just Taking Progesterone Not as Effective?

As you well know, adding progesterone by itself has not produced the same results. This makes logical given:

Pregnenolone supports several routes, not simply progesterone.
Direct progesterone bypasses upstream neurosteroid balancing, thereby perhaps causing an excess in one area and a deficit in others.


Your example implies that cycling pregnenolone or changing frequency could maximize your outcomes and minimize adverse effects by means of optimizing Try weekly cycling or every-other-day dosage and track your reaction.

With any luck, this helps. Tell us what finds success for you.

Read this if you have time:

Pregnenolone and Progesterone for Men: Pharmacokinetics and Studies - Excel Male TRT Forum

"Pregnenolone can be administered orally, subcutaneously, intravenously, intranasally, and topically/transdermally. Oral pregnenolone has high metabolism and low bioavailability.28 It is lipophilic and readily crosses the blood brain barrier. There is very limited data on the...

www.excelmale.com

Pregnenolone and progesterone tests

Pregnenolone Lab Test at Discounted Labs

Pregnenolone test

www.discountedlabs.com

Progesterone test (LC/MS)

Progesterone blood test for men and women

www.discountedlabs.com

 

Thank you for the reply, I’ll take a read through the links you posted.

 

Hi all,
I've been experimenting with pregnenolone for over a year now, with varied success. I seem to get benefits at 100mg (such as higher libido, more pronounced nighttime erections and better sleep); however, I don't get these results consistently. If I try to continue 100mg daily, the effects start waning by the second day (my theory for this is possibly progesterone elevating too high). I've also tried lowering the dose to 10mg, 25mg and 50mg; however, oddly enough, I only seem to get the benefits at 100mg. Extended use at the other doses eventually builds up and produces only negative effects. Anyway, I was wondering if anybody could clarify the half-life of pregnenolone, its sulfate derivative, and its conversion to progesterone and could offer any insight on dosing frequency.

By the way, I've experimented with just progesterone, but the benefits are less pronounced, and I become more susceptible to the negative effects.

(sorry for the long-winded ramble)

Pregnenolone taken in one large dose will convert more heavily to progesterone and pregnenolone sulfate

Compound this with no LH hormone while on trt and it is very likely to increase pregnenolone sulfate which agonizes nmda receptors.

this is why taking pregnenolone in large doses is not reliable especially while on trt. LH is needed to ensure proper conversion of pregnenolone. Hcg likely spurs conversion of these hormones but likely in different ratios than normal pulsatile LH.

An adult roughly makes around 30mg per day. Oral pregnenolone is converted into other steroids in different ratios than normal endogenously secreted pregnenolone. Largely through its metabolism in the liver.

what may be more beneficial is to break up your dosage into 3x daily. The smaller amount will convert in a more favorable ratio between pregnenolone sulfate, progesterone, and dhea.

 

A related question... since the Testosterone, that pregnenolone produces, is now replaced by exogenous T, does that not reduce the amount of pregnenolone we would need to supplement. If we normally make 30mg/day how much of that would be responsible for T production?

 

Pregnenolone taken in one large dose will convert more heavily to progesterone and pregnenolone sulfate

Compound this with no LH hormone while on trt and it is very likely to increase pregnenolone sulfate which agonizes nmda receptors.

this is why taking pregnenolone in large doses is not reliable especially while on trt. LH is needed to ensure proper conversion of pregnenolone. Hcg likely spurs conversion of these hormones but likely in different ratios than normal pulsatile LH.

An adult roughly makes around 30mg per day. Oral pregnenolone is converted into other steroids in different ratios than normal endogenously secreted pregnenolone. Largely through its metabolism in the liver.

what may be more beneficial is to break up your dosage into 3x daily. The smaller amount will convert in a more favorable ratio between pregnenolone sulfate, progesterone, and dhea.

Thank you for the response; I'll give it a try.

Btw the agonism of the NMDA receptors is interesting, as the negative symptoms I experience are very similar to my experiences with glycine.

 

Thank you for the response; I'll give it a try.

Btw the agonism of the NMDA receptors is interesting, as the negative symptoms I experience are very similar to my experiences with glycine.

Please let us know what happens!

 

Following, I have some on order...

 

What’s the most anyone here has taken per day? What would be the side effects? I take 100 mg pregnenolone a day and 50 mg dhea. I can’t tell any difference with or without taking them.

 

This study is starting at 50 mg twice per day and ramping up to 250 mg twice per day

A Neurosteroid Intervention for Menopausal and Perimenopausal Depression​

 

This one ramped dose up to 500 mg per day:

Pregnenolone reduces depression- Placebo controlled study - Excel Male TRT Forum

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression by Brown, E Sherwood; Park, John; Marx, Christine E; Hynan, Linda S; Gardner, Claire; Davila, Domingo; Nakamura, Alyson; Sunderajan, Prabha; Lo, Alexander; Holmes, Traci Neuropsychopharmacology. 2014...

www.excelmale.com

 

I am up to 100 mg twice per day. Two things I have noticed: deeper sleep and more fluidity in my speech. Watching closely to rule out the "placebo effect" that usually happens when we all start something new.

My pregnenolone on 100mg per day increased from almost undetectable to 95 ng/dL using a sensitive assay. I am hoping 200 mg may double that.

The "normal" range of pregnenolone in men is 10-200 ng/dL.

 

400 mg per day given in this study (compounded by Belmar Pharmacy in Colorado):

"We used a novel probe of emotion processing, modulation and regulation to assess the neural basis of allopregnanolone’s impact on emotion processing. We demonstrate that elevation of allopregnanolone following pregnenolone administration is associated with reduced activity in regions linked to the generation of negative emotion, increased activity in regions linked to regulatory processes, and enhancement of functional connectivity; an effect that is associated with less self-reported anxiety. To our knowledge, this is the first neuroimaging study to demonstrate an effect of allopregnanolone on emotion regulation, a function likely dysregulated in anxiety disorders. These findings add to the current knowledge regarding the effects of allopregnanolone on emotion neurocircuits, and provide neuroimaging evidence that allopregnanolone may modulate neurocircuits in directions counter to those observed in anxiety psychopathology.

Pregnenolone administration reduced activity in neural circuits associated with the generation of negative emotions. Across all conditions and all face types, pregnenolone administration decreased right amygdala and right insula activity, and serum levels of pregnenolone and allopregnanolone were negatively correlated with amygdala and insula activation levels. The amygdala is a key region in threat detection (52), fear conditioning (53), and emotional salience (54). The insula is responsible for interoception (55), disgust (56), emotion processing (57), emotional recall (36), and anticipation of aversive stimuli (58). Both regions are associated with negative emotional response (57), and greater amygdala activation in response to the presentation of facial expressions is associated with greater magnitude of emotional response (59–63). Additionally, activation reductions in amygdala and insula are associated with down-regulation of negative emotions (64). Thus, allopregnanolone’s reduction of activity in amygdala and insula suggests that allopregnanolone may reduce emotional reactivity to aversive stimuli.

Pregnenolone administration also increased activity in the dmPFC, a region linked to regulatory control over emotion. This finding was specific to the appraisal condition. We have previously demonstrated that shifting attention to become aware of and evaluate the intensity of one’s emotional response to aversive stimuli leads to robust activation of dmPFC and rostral ACC (59, 65–67). Behavioral studies of emotional appraisal and labeling report that this strategy lowers distress (68) and facilitates habituation (69). Thus, allopregnanolone’s enhancement of dmPFC activity during appraisal suggests that allopregnanolone may facilitate the evaluation of one’s own emotional response and aid in successful down-regulation of negative emotions. Interestingly, greater dmPFC activity during appraisal was associated with greater self-reported anxiety. As the dmPFC is central to conscious threat appraisal (70), greater dmPFC activity in individuals with higher self-reported anxiety could reflect greater levels of threat processing. Alternatively, higher activity in this region could reflect greater task engagement in certain individuals.

Finally, pregnenolone administration increased connectivity between amygdala and dmPFC during appraisal, with greater connectivity associated with reduced self-reported anxiety. Psychophysiological interaction (PPI) reflects the connectivity between one region and another during a particular context, controlling for the baseline relationship between regions. Thus, the current results suggest that allopregnanolone is associated with greater functional coupling between amygdala and dmPFC during appraisal specifically. However, PPI does not assess the impact of third-party regions on the two regions of interest, and does not reflect causal relationships. While these correlational findings do not necessarily provide evidence of an inhibitory or excitatory relationship, they may suggest potential neural mechanisms of emotional regulation given known structural connections and reciprocal feedback loops between amygdala and mPFC (71–73). Previous research indicates that emotion regulation depends on interactions between dmPFC and amygdala (74). At least one previous study has demonstrated that enhanced connectivity between dmPFC and amygdala is associated with successful emotion regulation and less negative affect (75). Of note, some evidence suggests that successful regulation is associated with an inverse relationship (anti-correlation) between dmPFC and amygdala (64, 76). However, in our sample, greater connectivity between amygdala and dmPFC was associated with less self-reported anxiety, suggesting allopregnanolone’s modulatory effects on connectivity may aid dmPFC-mediated appraisal and/or reduce amygdala-mediated negative emotional responding. Our findings extend those of Van Wingen and colleagues (34) by demonstrating that allopregnanolone’s selective enhancement of dmPFC to amygdala connectivity is associated with reduced anxiety. Since several anxiety disorders are characterized by a lack of neural regulatory control (77) and impaired emotion regulation (38), future studies should examine allopregnanolone’s potential as a neurosteroid target for pharmacologic intervention for these individuals.

Allopregnanolone likely impacts emotion regulation neurocircuitry through GABAergic mechanisms, though it may also impact this circuitry through its enhancement of neurogenesis (78) myelination (79) or neuroprotection (80–83). Amygdala and mPFC are rich in GABA(A) receptors (28) and endogenous allopregnanolone (48), suggesting that allopregnanolone could feasibly have a direct impact on activity in these regions. Indeed, in our sample, allopregnanolone serum level was more strongly correlated to amygdala activity than activity in any other brain region. Preclinical research suggests that the amygdala may be a particular target of allopregnanolone’s anxiolytic effects (30). In rats, microinfusions of allopregnanolone directly into the amygdala produce anxiolytic (30) antidepressant (31) and anti-aggressive (32) effects. In previous neuroimaging studies, greater endogenous allopregnanolone has been reported to be associated with lower amygdala reactivity (33, 41) and greater coupling between amygdala and dmPFC (34). Though we did not directly test the GABAergic effect of our intervention, our findings illuminate potential neural pathways through which pregnenolone administration and resulting increases in allopregnanolone levels could feasibly impact GABAergic transmission in a manner that is relevant to pathological anxiety."

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits - PMC

The neurosteroid allopregnanolone is a potent allosteric modulator of the GABA(A) receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective ...

www.ncbi.nlm.nih.gov

 

I am going to ask Empower to make 250 mg capsules since they now produce smaller doses:

Pregnenolone Capsules

Choose Empower Pharmacy for compounded Pregnenolone Capsules. The leading accredited 503A and FDA-registered 503B compounding pharmacy.

www.empowerpharmacy.com

 

I am up to 100 mg twice per day. Two things I have noticed: deeper sleep and more fluidity in my speech. Watching closely to rule out the "placebo effect" that usually happens when we all start something new.

My pregnenolone on 100mg per day increased from almost undetectable to 95 ng/dL using a sensitive assay. I am hoping 200 mg may double that.

The "normal" range of pregnenolone in men is 10-200 ng/dL.

Are you also taking dhea? And if so how much per day?

 

No DHEA. TRT has very little effect on DHEA and my levels are usually mid range. The data on DHEA and mood is all over the place. Not a strong believer.

 

I am up to 100 mg twice per day. Two things I have noticed: deeper sleep and more fluidity in my speech. Watching closely to rule out the "placebo effect" that usually happens when we all start something new.

My pregnenolone on 100mg per day increased from almost undetectable to 95 ng/dL using a sensitive assay. I am hoping 200 mg may double that.

The "normal" range of pregnenolone in men is 10-200 ng/dL.

No negative effects that u’ve noticed? It hasn’t effected sexual function negatively at all?

 

@Nelson Vergel do u know if pregnenolone raises E2 by any chance?

 

So just to be clear do you take pregenolone with hcg or in place of it ?

 

@Nelson Vergel do u know if pregnenolone raises E2 by any chance?

Have not seen any increase in E2. Pregnenolone is so far up in the cascade.