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.

 

No.

Even though when you see this diagram it only makes sense to infer that supplementing pregnenolone and DHEA may increase testosterone, the fact is that, for that to happen, the enzymes responsible for synthesis of downstream hormones may be affected by several factors.

View attachment 46686

Sex Hormone Cascade from Pregnenolone to Testosterone​

The synthesis of sex hormones, including testosterone, follows a complex cascade starting from cholesterol. Here is a detailed overview of the pathway from pregnenolone to testosterone:

1. Conversion of Cholesterol to Pregnenolone​

The process begins in the mitochondria, where cholesterol is converted into pregnenolone by the enzyme cholesterol side-chain cleavage enzyme (CYP11A1). This step is crucial as pregnenolone serves as the precursor for all steroid hormones.

2. Conversion of Pregnenolone to 17α-Hydroxypregnenolone​

Pregnenolone is then converted into 17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (CYP17A1). This enzyme is found in the adrenal glands and gonads.

3. Conversion to Dehydroepiandrosterone (DHEA)​

The same enzyme, CYP17A1, also possesses 17,20-lyase activity, which converts 17α-hydroxypregnenolone into dehydroepiandrosterone (DHEA).

4. Conversion of DHEA to Androstenedione​

DHEA is then converted into androstenedione by the enzyme 3β-hydroxysteroid dehydrogenase (HSD3B2). This conversion is a critical step as androstenedione is a direct precursor to testosterone.

5. Conversion of Androstenedione to Testosterone​

Finally, androstenedione is converted into testosterone by the enzyme 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3). This enzyme facilitates the reduction of androstenedione to testosterone, completing the cascade.

Enzymatic Pathway Summary​

Step	Substrate	Enzyme	Product
1	Cholesterol	CYP11A1	Pregnenolone
2	Pregnenolone	CYP17A1	17α-Hydroxypregnenolone
3	17α-Hydroxypregnenolone	CYP17A1 (17,20-lyase)	DHEA
4	DHEA	HSD3B2	Androstenedione
5	Androstenedione	HSD17B3	Testosterone

Physiological Significance​

This cascade is essential for the production of testosterone, a critical androgen responsible for male sexual development, reproductive function, and various other physiological processes. Disruptions in any step of this pathway can lead to hormonal imbalances and associated health issues.Understanding this pathway is crucial for medical research and treatment strategies involving hormone replacement therapy, fertility treatments, and managing conditions related to hormonal imbalances.

Factors that Affect Downstream Conversion

Several factors can affect the activity of enzymes that convert sex hormones into downstream ones. These factors include:

1. Hormonal Regulation​

• Feedback Mechanisms: Hormones can regulate enzyme activity through feedback loops. For example, high levels of end products like testosterone can inhibit upstream enzymes to maintain balance.
• Other Hormones: Hormones like follicle-stimulating hormone (FSH) and luteinizing hormone (LH) can activate or inhibit enzymes like aromatase, which converts androgens to estrogens.

2. Genetic Factors​

• Gene Expression: Variations in the genes encoding steroidogenic enzymes can affect their expression levels and activity. Polymorphisms in the CYP17A1 gene, for example, can change how much 17α-hydroxylase is made, which in turn changes pregnenolone into other hormones.
• Mutations: Mutations in genes like HSD17B3 can lead to deficiencies in enzymes responsible for converting androstenedione to testosterone, resulting in hormonal imbalances.

3. Local Tissue Factors​

• Tissue-Specific Expression: The expression of enzymes like aromatase can vary between tissues, affecting local hormone levels. For example, aromatase is highly expressed in adipose tissue, influencing local estrogen production.
• Cellular Environment: The redox state, pH, and availability of cofactors (e.g., NADPH) in the cellular environment can influence enzyme activity. For example, oxidative stress can inhibit steroidogenic enzymes by altering the redox balance.

4. Age and Developmental Stage​

• Aging: The efficiency of steroidogenic enzymes can decline with age, affecting hormone production. For instance, aging can reduce the activity of enzymes in Leydig cells, leading to lower testosterone levels.
• Developmental Changes: Hormone production and enzyme activity can vary during different life stages, such as puberty, pregnancy, and menopause.

5. Environmental Factors​

• Endocrine Disruptors: Exposure to environmental chemicals like bisphenol A (BPA) and phthalates can disrupt the activity of steroidogenic enzymes, leading to altered hormone levels.
• Diet and Lifestyle: Nutritional status and lifestyle factors such as stress and physical activity can influence hormone production and enzyme activity.

6. Disease States​

• Cancer: Enzymes like 17β-hydroxysteroid dehydrogenases (HSD17B1 and HSD17B2) can change how they are expressed and work in diseases like breast cancer. This can affect hormone levels in the area and the progression of the disease.
• Metabolic Disorders: Conditions such as obesity and diabetes can affect the activity of steroidogenic enzymes, leading to imbalances in hormone levels.

Understanding these factors is crucial for developing targeted therapies and managing conditions related to hormonal imbalances.

Thank you, Nelson.

 

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.

Are you still anti-DHEA? And are you still supplementing with Pregnenolone? And if so, at what dose? And are you on HCG?

 

Are you still anti-DHEA? And are you still supplementing with Pregnenolone? And if so, at what dose? And are you on HCG?

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

 

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

Have you felt a better response from 500 IU versus 250IU? I’ve been doing 250 IU twice weekly for a while but been contemplating going up? Just worried about higher E2.

And do you feel like you’re getting enough DHEA conversion from the Pregnenolone? I would love to just take pregnenolone if I could! I currently take 30 mg Preg and 25 mg DHEA. Unfortunately whenever I start taking Pregnenolone, I feel better emotionally and mentally but then my libido tanks…..

And I’m surprised your Test dose is so low?

What do these doses keep your total and free at?

 

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

What Preg product are you using right now?

 

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.

Were you taking HCG as well? And if so, how much was your dose?

 

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

What does this protocol keep your Total, Free and E2 at?

 

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

I've just taken 50mg pregnenolone before bed for the first time and actually slept worse. I felt more awake and alert like I wasn't tired, the opposite of what I was hoping to achieve.

Could this just be a symptom of addressing a deficiency for the first time, or is this a typical outcome for some people?

 

I've just taken 50mg pregnenolone before bed for the first time and actually slept worse. I felt more awake and alert like I wasn't tired, the opposite of what I was hoping to achieve.

Could this just be a symptom of addressing a deficiency for the first time, or is this a typical outcome for some people?

It is very difficult to predict anyone's response to any hormone treatment. Have you tried taking it during the day?

 

It is very difficult to predict anyone's response to any hormone treatment. Have you tried taking it during the day?

Not yet, this was my first dose ever on the advice of Defy.

I'm trying to decide whether to try some in the morning today or just stay the course and do what was recommended by my provider.

If it brought on more energy and wakefulness, I'd certainly be interested in that during waking hours.

 

Only Preg at 50 mg per night. HCG 500 IU twice per week. TRT 50 mg testosterone enanthate twice per week.

What does your total, free and e2 sit at on this protocol?