Pregnenolone & Progesterone Are Both Agonists Of The Androgen Receptor

haidut

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Patients with prostate cancer are often treated with a combination of therapies such as 5-AR inhibitors to reduce production of DHT as well as other enzyme inhibitors to reduce conversion of DHEA into other downstream androgens. From the point of view of mainstream "treatment" for prostate cancer EVERY androgen is suspect, no matter how weak of an agonist it is of the androgen receptor. In recent years, the term "castration resistant cancer" has been coined to describe patients whose tumors continue to grow despite the androgen depletion therapy. So, mainstream medicine began to look for new culprits further up the chain of steroids. While this witch hunt is on the completely wrong path, it does provide some valuable bits of information to us laymen - i.e. what steroids have (previously unsuspected) androgenic effects.
I have long suspected that pregnenolone (at least in low doses) has androgenic effects. This is one of the reason for me to include it in the Pansterone supplement. I did not have much evidence go to by but there was one study showing pregnenolone to be a potent androgen in the prostate when used in concentrations of 500nM. However, that study used the so-called "mutated androgen receptor" as found in prostate cancer cells and as such was not applicable to the general population. However, this new study found that pregnenolone and progesterone BOTH act as agonists at the androgen receptor and the concentrations used were much lower - only 10nM of each steroid, which puts them barely above physiological levels. There are a number of studies published in the 1970s that showed pregnenolone and progesterone can maintain prostate size and fertility in castrated animals but at the time there was no plausible mechanism known. Now, with the more recent studies it seems that pregnenolone and progesterone both have androgenic activity and this is yet another mechanism through which both steroid oppose estrogen.

http://www.jurology.com/article/S0022-5347(13)02178-2/fulltext#sec0010

"...Higher, supraphysiological levels of Prog and Preg (10 nM) were required to induce VCaP cell growth, which could be blocked by antiandrogens. Similarly, parental DuCaP cell growth was stimulated by Prog and Preg (10 nM). CYP17A1 siRNA as well as the selective 17,20-lyase activity inhibitor orteronel were unable to block Prog- or Preg-induced cell growth of VCaP and DuCaP. Incubation of VCaP cells with Prog (100 nM) induced AR target gene expression, which was not inhibited by si-CYP17A1 or orteronel. Enzymatic profiles of CRPC clones showed that CYP17A1 mRNA was increased in most of the clones. The growth of these CRPC clones, however, was not affected by the addition of orteronel. In Hep3B cells, Preg and Prog induced translocalization of AR to the nucleus, which was not affected by the addition of orteronel."

"...CYP17A1 blockade was not relevant to Prog- or Preg-induced cell growth in VCaP and DUCaP cells and Preg- and Prog-induced translocalization of AR in Hep3B cells. CYP17A1 and AR mRNA over-expression in CRPC clones of VCaP and DuCaP did not relate to enhanced CRPC cell growth. These data suggest that the growth stimulation of VCaP and DUCaP cells by Prog and Preg may be driven by direct activation of the over-expressed AR."

Now, the question becomes how potent either one of the steroids is in respect to activating the androgen receptor and what doses in vivo would be required to produce these effects. The study in mutated androgen receptors I mentioned earlier shed some light on these questions. It confirms that it is pregnenolone (and not one if its metabolites) directly that has androgenic effects and that androgenic effects were almost the same as those of DHT. Pregnenolone had similar binding affinity for the androgen receptor to the highly potent synthetic androgen R1881 (Metribolone - Wikipedia). The HED of pregnenolone tested in vivo that study was about 3.5mg/kg daily, which means for most people that would mean 250mg - 350mg pregnenolone daily.

Pregnenolone stimulates LNCaP prostate cancer cell growth via the mutated androgen receptor. - PubMed - NCBI
"...Further studies were also performed with the conjugated pregnenolone, P5-S, which is unable to cross the cell membrane. P5-S (0.2–20 nM) had no effect on the growth of LNCaP prostate cancer cells (data not shown). These results suggested that the growth-stimulatory effects of P5 on LNCaP cells were being mediated directly by the steroid itself and not by the metabolites (Fig. 2), and that, in order to illicit its effects, P5 has to enter the cell."

"...In situ photolabeling was performed to determine the size of the P5 cellular-binding site. Using this method, a major peak at approximately 110 kDa (size of AR [25]) was recorded for R1881 and P5 (data not shown). This suggests that P5 may be binding to the same site as R1881, that is the LNCaPAR."

"...Cells were treated with DHT or P5 and the effects of these steroids on luciferase production were determined. DHT (5 nM) stimulated luciferase production mediated by the wildtype androgen receptor by 4-fold compared with the control, whereas P5 (5 nM) did not have any effect on luciferase production in CV1-LUC/p5CMV-hAR cells (Fig. 6A). In cells transfected with the mutated LNCaPAR, both DHT and P5-stimulated luciferase production by 2.2-fold and 1.8-fold vs. control, respectively (Fig. 6B). These results suggest that the growth stimulatory effects of P5 on LNCaP cells are being mediated by the mutated AR."
"...Only progesterone and P5, at their physiological concentrations, were able to stimulate LNCaP-cell growth at a level comparable with that of the androgens, DHT and testosterone. P5, a common precursor of all steroid hormones, is present in the blood of normal adult men at a concentration of 1–3 nM [18–20]. We found that, at a 2-nM concentration, P5-stimulated LNCaP-cell proliferation 7–8-fold. In addition, a subphysiological concentration of P5 (0.2 nM) was also growth stimulatory to the cells (3–4-fold increase in cell number compared with vehicle-treated cells)."
"...Moreover, the similar Bmax values obtained with R1881 (0.07 pmol/mg protein) and P5 (0.063 pmol/mg protein) suggest that both ligands bind to the same receptor. The in situ-photolabeling studies [3] support this suggestion by revealing a similar pattern of protein binding for the synthetic androgen, R1881, and for P5 in LNCaP-cellular lysate, which confirmed that P5 was binding to the mutated LNCaPAR."
 
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Tarmander

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Interesting...I am curious how Progesterone can be both an anti androgen as well as a pro androgen? Usually you hear about it being an anti androgen at higher doses and pro androgen at lower doses. What does this suggest? Does progesterone have a weaker affinity for androgens at different doses?
 

DaveFoster

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Interesting...I am curious how Progesterone can be both an anti androgen as well as a pro androgen? Usually you hear about it being an anti androgen at higher doses and pro androgen at lower doses. What does this suggest? Does progesterone have a weaker affinity for androgens at different doses?
Same here.
 

haidut

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Interesting...I am curious how Progesterone can be both an anti androgen as well as a pro androgen? Usually you hear about it being an anti androgen at higher doses and pro androgen at lower doses. What does this suggest? Does progesterone have a weaker affinity for androgens at different doses?

I updated the original post with some extra information. The in vivo model used a HED of 250mg - 350mg daily, which definitely not a low dose. So, not sure at what point pregnenolone starts behaving as an anti-androgens. Anti-androgenic effects from pregnenolone are probably due to its conversion into progesterone and allopregnanolone into which pregnenolone mostly converts when given to humans in doses of 400mg - 500mg daily. It could be that progesterone and pregnenolone are capable of acting like ANY steroid that the specific tissue needs at any given moment. This is what Selye thought and hinted to as shown in the study I posted in the original Pansterone thread. Selye thought that pregnenolone can potentiate the effects of endpoint steroids when administered together with them. Given the studies that it can substitute for androgens (partially) in castrated animals than that is probably its role - i.e. pregnenolone is truly the Pan-steroid that is not only a precursor to all other steroids but can also probably fulfill the role of any of them (at least partially) when the needed steroid is absent due to various pathologies. The studies with pregnenolone and rheumatoid arthritis in the 1930s and 1940s also found that pregnenolone had the anti-inflammatory effects of cortisol but without actually converting into cortisol. So, the suggestions to take pregnenolone for virtually ANY steroid imbalance may be quite on point. But maybe not due to pregnenolone converting into the desired steroid so much as due to the its ability to bind to pretty much any steroid "receptor" and act as a temporary mimetic for the missing steroid.
Just my 2c.
 
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haidut

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DaveFoster

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I updated the original post with some extra information. The in vivo model used a HED of 250mg - 350mg daily, which definitely not a low dose. So, not sure at what point pregnenolone starts behaving as an anti-androgens but based on the studies it is probably not acting as an anti-androgen in any concentrations. Anti-androgenic effects, if any, from pregnenolone are probably due to its conversion into allopregnanolone into which pregnenolone mostly converts when given to humans in doses of 400mg - 500mg daily. Progesterone may also play an anti-androgenic role but it is probably minor and may not even be relevant given its androgenic effects in prostate as per the 2 studies above. It could be that progesterone and pregnenolone are capable of acting like ANY steroid that the specific tissue needs at any given moment. This is what Selye thought and hinted to as shown in the study I posted in the original Pansterone thread. Selye thought that pregnenolone can potentiate the effects of endpoint steroids when administered together with them. Given the studies that it can substitute for androgens completely in castrated animals than that is probably its role - i.e. pregnenolone is truly the Pan-steroid that is not only a precursor to all other steroids but can also probably fulfill the role of any of them (at least partially) when the needed steroid is absent due to various pathologies. The studies with pregnenolone and rheumatoid arthritis in the 1930s and 1940s also found that pregnenolone had the anti-inflammatory effects of cortisol but without actually converting into cortisol. So, the suggestions to take pregnenolone for virtually ANY steroid imbalance may be quite on point. But not due to pregnenolone converting into the desired steroid so much as due to the its ability to bind to pretty much any steroid receptor and act as a temporary mimetic for the missing steroid.
Just my 2c.
Awesome; good reason to take pregnenolone until the day you die.
 

Regina

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I updated the original post with some extra information. The in vivo model used a HED of 250mg - 350mg daily, which definitely not a low dose. So, not sure at what point pregnenolone starts behaving as an anti-androgens but based on the studies it is probably not acting as an anti-androgen in any concentrations. Anti-androgenic effects, if any, from pregnenolone are probably due to its conversion into allopregnanolone into which pregnenolone mostly converts when given to humans in doses of 400mg - 500mg daily. Progesterone may also play an anti-androgenic role but it is probably minor and may not even be relevant given its androgenic effects in prostate as per the 2 studies above. It could be that progesterone and pregnenolone are capable of acting like ANY steroid that the specific tissue needs at any given moment. This is what Selye thought and hinted to as shown in the study I posted in the original Pansterone thread. Selye thought that pregnenolone can potentiate the effects of endpoint steroids when administered together with them. Given the studies that it can substitute for androgens completely in castrated animals than that is probably its role - i.e. pregnenolone is truly the Pan-steroid that is not only a precursor to all other steroids but can also probably fulfill the role of any of them (at least partially) when the needed steroid is absent due to various pathologies. The studies with pregnenolone and rheumatoid arthritis in the 1930s and 1940s also found that pregnenolone had the anti-inflammatory effects of cortisol but without actually converting into cortisol. So, the suggestions to take pregnenolone for virtually ANY steroid imbalance may be quite on point. But not due to pregnenolone converting into the desired steroid so much as due to the its ability to bind to pretty much any steroid receptor and act as a temporary mimetic for the missing steroid.
Just my 2c.
My rat is taking 100mg pregnenolone in the morning then another 100mg pregnenolone plus androsterone post-aikido training. She loves it.
She's kind of a hollow leg with everything else she's getting (don't notice any difference). But not with this (for my rat) noticeable combo.

She does't have any carotemia at all anymore. But is getting thicker in the mid-section. Training was intense tonight and she had an ammonia smell when the training intensity increased. :wtf: She was not fed meat today - just an omelette, hot chocolate milk and OJ in the afternoon before training.

So, I think there is still some "pathology" in not metabolizing the sugar at an efficient rate and she sucks down pregnenolone/androsterone to feel great.
 

Tarmander

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I updated the original post with some extra information. The in vivo model used a HED of 250mg - 350mg daily, which definitely not a low dose. So, not sure at what point pregnenolone starts behaving as an anti-androgens but based on the studies it is probably not acting as an anti-androgen in any concentrations. Anti-androgenic effects, if any, from pregnenolone are probably due to its conversion into allopregnanolone into which pregnenolone mostly converts when given to humans in doses of 400mg - 500mg daily. Progesterone may also play an anti-androgenic role but it is probably minor and may not even be relevant given its androgenic effects in prostate as per the 2 studies above. It could be that progesterone and pregnenolone are capable of acting like ANY steroid that the specific tissue needs at any given moment. This is what Selye thought and hinted to as shown in the study I posted in the original Pansterone thread. Selye thought that pregnenolone can potentiate the effects of endpoint steroids when administered together with them. Given the studies that it can substitute for androgens completely in castrated animals than that is probably its role - i.e. pregnenolone is truly the Pan-steroid that is not only a precursor to all other steroids but can also probably fulfill the role of any of them (at least partially) when the needed steroid is absent due to various pathologies. The studies with pregnenolone and rheumatoid arthritis in the 1930s and 1940s also found that pregnenolone had the anti-inflammatory effects of cortisol but without actually converting into cortisol. So, the suggestions to take pregnenolone for virtually ANY steroid imbalance may be quite on point. But not due to pregnenolone converting into the desired steroid so much as due to the its ability to bind to pretty much any steroid receptor and act as a temporary mimetic for the missing steroid.
Just my 2c.

Thank you very much for the write up.
 
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My rat is taking 100mg pregnenolone in the morning then another 100mg pregnenolone plus androsterone post-aikido training. She loves it.
She's kind of a hollow leg with everything else she's getting (don't notice any difference). But not with this (for my rat) noticeable combo.

She does't have any carotemia at all anymore. But is getting thicker in the mid-section. Training was intense tonight and she had an ammonia smell when the training intensity increased. :wtf: She was not fed meat today - just an omelette, hot chocolate milk and OJ in the afternoon before training.

So, I think there is still some "pathology" in not metabolizing the sugar at an efficient rate and she sucks down pregnenolone/androsterone to feel great.
I developed a belly over the last 3 months...never had one before! I would say it's about as long as I have been taking pregnenelone, and progesterone. But I also added more sugar and calories, so how do you know what's really going on? Please keep it on a simple level ;-)
 

Regina

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I developed a belly over the last 3 months...never had one before! I would say it's about as long as I have been taking pregnenelone, and progesterone. But I also added more sugar and calories, so how do you know what's really going on? Please keep it on a simple level ;-)
Brothers keeper,
Brighter minds than mine will hopefully chime in.
An update of my feedback: I experienced the same as you wrt weight gain in mid-section. But also sleeping later.
This seems to have settled down a bit. I may have even lost a couple of the pounds I gained. This is concurrent to my training going a tad lighter.
(to maybe four 1 hr aikido classes per week).
So, I am not at all worried and very happy with how I feel and respond to life. For example, rapid rebound from stressful events.
Carotemia came and went.
Intolerance to OJ came and went.
Weight gain came and is possibly starting to reverse course.
Another thing is virtually everyone around me caught a bug going around Chicago. In both dojos I was attending, work colleagues, family... all had some sort of cold-like thing. I did not get it at all.

Staying the course. I love the way pregnenolone and androsterone make me feel.
 

aarfai

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Has any male had success using Progesterone to increase androgens and/or libido?
 

aarfai

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Libido went through the roof from low dose up to 4mg, don't know the effect of overall androgens. I used it no more than a week.
Were you using Haidut's Progestene? And where did you apply it?

Why did you stop if you don't mind me asking...
 
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I experienced the same as you wrt weight gain in mid-section. But also sleeping later.
Thank you for your thoughtful reply. Problem is it's usually called a cortisol belly, which means more stress on the adrenals. And it immobilized me. Threw my balance off kilter. Since I've cut back on the excess sugar, it's slowly going away. Still eating fruit. With nuts(to mitigate the insulin response)...yeah, I know...all those nuts on the tree are just for the squirrels. poor things...all that PUFA!! (And just so no one will cast stones and say that the almonds caused the problem, I wasn't eating them or any other PUFA'S when I developed the belly. I have just very recently started eating them again. :)
 

Drareg

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Brothers keeper,
Brighter minds than mine will hopefully chime in.
An update of my feedback: I experienced the same as you wrt weight gain in mid-section. But also sleeping later.
This seems to have settled down a bit. I may have even lost a couple of the pounds I gained. This is concurrent to my training going a tad lighter.
(to maybe four 1 hr aikido classes per week).
So, I am not at all worried and very happy with how I feel and respond to life. For example, rapid rebound from stressful events.
Carotemia came and went.
Intolerance to OJ came and went.
Weight gain came and is possibly starting to reverse course.
Another thing is virtually everyone around me caught a bug going around Chicago. In both dojos I was attending, work colleagues, family... all had some sort of cold-like thing. I did not get it at all.

Staying the course. I love the way pregnenolone and androsterone make me feel.

Haidut was speculating that pregnenolone can mimick any steroid hormone,if that's the case and it can mimick cortisol it could explain weight gain in that area. It's possible sore joints like he mentioned could be causing it to mimick cortisol and this could have knock on effects elsewhere,if you have sore joints of course,there are other reasons it could be increasing .
Wild speculation of course but might be worth knocking pregnenolone on the head if you feel calories are not the issue and seeing if the area improves.
 

BastiFuntasty

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Were you using Haidut's Progestene? And where did you apply it?

Why did you stop if you don't mind me asking...
Yes I did, well I just wanted to use it short term to bring stress down and than go on with preg dhea. And well progesterone in males, I wouldn't use it too often, a drop here a drop there a month that's what I do now.
 
L

lollipop

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Haidut was speculating that pregnenolone can mimick any steroid hormone,if that's the case and it can mimick cortisol it could explain weight gain in that area. It's possible sore joints like he mentioned could be causing it to mimick cortisol and this could have knock on effects elsewhere,if you have sore joints of course,there are other reasons it could be increasing .
Wild speculation of course but might be worth knocking pregnenolone on the head if you feel calories are not the issue and seeing if the area improves.
Was it any steroid hormone @Drareg or only the androgens? I am not clear if cortisol is an androgen or not. Forgive my lack of knowledge in this steroid area.
 
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