Pregnenolone Pharmacokinetics and Studies: Need for Backfilling Pathways for Men on TRT?

Nelson Vergel

Founder, ExcelMale.com
"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 pharmacokinetics of exogenous pregnenolone. Oral pregnenolone is metabolized in preference to allopregnanolone, rather than other hormones biosynthesized from pregnenolone substrate, such as 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 shows that a single oral dose of 175mg of pregnenolone approximately doubled pregnenolone serum levels over the course of four to eight hours.

One study 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. Treatment with oral pregnenolone elevated pregnenolone serum levels fourfold, pregnenolone sulfate serum levels tripled, and allopregnanolone serum levels increased fivefold. Furthermore, treatment with oral pregnenolone elevated progesterone serum levels more than fourfold and DHEAS levels by approximately 16%. In this study, exogenous pregnenolone did not increase serum levels of testosterone, free testosterone, cortisol, DHEA, estradiol, or androstenedione levels."

Marx CE, Keefe RSE, et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2009 Jul; 34(8): 1885–1903.

Note from Nelson


If men on TRT have undetectable or very low pregnenolone due to the LH shut down caused by TRT, then a dose close to 100 mg per day may actually increase pregnenolone blood levels one fold.
I am particularly interested in pregnenolone's boosting effect on allopregnanolone:




allopregnenolone production from pregnenolone.jpg
 
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Nelson Vergel

Founder, ExcelMale.com

A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression​

Neuropsychopharmacology. 2014 Nov; 39(12): 2867–2873.

Abstract
Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.

 

Nelson Vergel

Founder, ExcelMale.com
 

Gianluca

Active Member
Great post Nelson. Oral Progesterone is probably a more powerful tool to increase Allopregnenolone than Pregnenolone itself
 

anix

New Member
I use progesterone cream as an anxylotic and NAC as well. They help little. Im medically refractory MDD and BP. Ive been doing reading one Pregnenolone for cognitive and TBI benefit. My stuff are TBI related. Likely why I dont respond to the meds I was on for years. Thks for this post.
 

Nelson Vergel

Founder, ExcelMale.com
Great post Nelson. Oral Progesterone is probably a more powerful tool to increase Allopregnenolone than Pregnenolone itself
How much do you take? I tried it for a while but I retained too much water. It may be worth another try.

I have been taking 100 mg pregnenolone every night for a week. It may be too early to tell (placebo effect?), but I am sleeping well and my mood and energy have improved. Let's see if this effect is only happening by chance!

I am also taking iron plus vitamin C (1000 mg) to improve my low ferritin (it was 34 when I lasted checked)
 

Gman86

Member
How much do you take? I tried it for a while but I retained too much water. It may be worth another try.

I have been taking 100 mg pregnenolone every night for a week. It may be too early to tell (placebo effect?), but I am sleeping well and my mood and energy have improved. Let's see if this effect is only happening by chance!

I am also taking iron plus vitamin C (1000 mg) to improve my low ferritin (it was 34 when I lasted checked)
What brand of Pregnenolone are u taking?
 

Gianluca

Active Member
I use progesterone cream as an anxylotic and NAC as well. They help little. Im medically refractory MDD and BP. Ive been doing reading one Pregnenolone for cognitive and TBI benefit. My stuff are TBI related. Likely why I dont respond to the meds I was on for years. Thks for this post.

do you use the cream on a daily basis or as needed? capsule may work better as an anxiolytic, it should convert more into allopregnenolone because the first pass in the liver
 

Gianluca

Active Member
How much do you take? I tried it for a while but I retained too much water. It may be worth another try.

I have been taking 100 mg pregnenolone every night for a week. It may be too early to tell (placebo effect?), but I am sleeping well and my mood and energy have improved. Let's see if this effect is only happening by chance!

I am also taking iron plus vitamin C (1000 mg) to improve my low ferritin (it was 34 when I lasted checked)

I have been experimenting for a little bit with 5mg micronized cap from Empower, it has a mild sedating effect for me, it helped me with social anxiety better than Pregnenolone I believe, but still need to experiment more to confirm this. With the 5mg I did not notice any water retention or decrease libido/sex drive. I tried 10mg for the past two days at night, and the sedating effect definitely increased.

That sounds like you getting the good side effects of Pregnenolone! I have personally seen with myself within a week/10 days the effect of oral neurosteroids stabilizing, that may not be placebo

why not eating red meat regularly for Iron instead of the supplement? in my opinion is a better choice. I have seen my Ferritin increasing over the time when I started to use about 3gr or more of pure ascorbic acid, and I even take it on an empty stomach
 

Nelson Vergel

Founder, ExcelMale.com
What brand of Pregnenolone are u taking?
pregnenolone supplement excelmale.jpg

I just got my pre-pregnenolone supplementation level (by LC/MS assay). My pregnenolone test level was 11 ng/dL (Quest "normal" range 22-237 ng/dL). I will retest in a few weeks after taking 100 mg every night. My progesterone test level (immunoassay) was 0.7 ng/mL (no range given). Let's see how much progesterone increases due to pregnenolone supplementation.
 

Nelson Vergel

Founder, ExcelMale.com
I created this panel to look at upstream and downstream hormones for men on TRT:

 

DixieWrecked

Active Member
View attachment 14631

I just got my pre-pregnenolone supplementation level (by LC/MS assay). My pregnenolone test level was 11 ng/dL (Quest "normal" range 22-237 ng/dL). I will retest in a few weeks after taking 100 mg every night. My progesterone test level (immunoassay) was 0.7 ng/mL (no range given). Let's see how much progesterone increases due to pregnenolone supplementation.
You are a saint. I am excited to see the data.
 

Gman86

Member
View attachment 14631

I just got my pre-pregnenolone supplementation level (by LC/MS assay). My pregnenolone test level was 11 ng/dL (Quest "normal" range 22-237 ng/dL). I will retest in a few weeks after taking 100 mg every night. My progesterone test level (immunoassay) was 0.7 ng/mL (no range given). Let's see how much progesterone increases due to pregnenolone supplementation.
I love when guys get labs before and after trying things, can’t wait to see how the 100mg of pregnenolone effects ur pregnenolone and progesterone levels.

The range for progesterone is usually (0.0-0.5 ng/ml). It used to be (0.0-1.0). So ur level is actually quite good. From my understanding a good range to keep progesterone in would be between 0.8-1.2, for males. I’m assuming ur level is decent due to the HCG that ur taking. Mine usually comes back around 0.1 ng/ml on testosterone alone. HCG has brought it up quite a bit in the past, I forget exactly how much HCG raised it. Would have to look back at old labs

This was a pretty good quick video on progesterone lab testing, IIRC. I think he likes to see males around the 1.2 ng/ml range, again if IIRC
 

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