RP Email Advice Comment: 5-Alpha Dihydroprogesterone

[goodandevil]

Ray is anticommercial (to a fault). The framing of the question "yo this new stuff just hit the streets today" alone will trigger him. And it is perfectly reasonable to warn against novel substances he probably hasn't read about yet in depth. Everyone buys these things at their own risk. The true method of knowledge is experiment.

You really think he's that fragile?

 

[moriwatzi]

Not fragile, angry. He had enough bad experiences in this area.

 

[lollipop]

I like these critical discussions but I can't help but feel you are going out of your way to denigrate Haidut, and setting Peat up to do it with you.

I agree with this wholeheartedly! Interesting conversations and they also seem a bit like a move to discredit Haidut without a thorough full sided discussion about the topics. It would be fascinating to try and facilitate an actual recorded conversation between Haidut and Ray on these individual substances after each (Ray and Haidut) have been provided the full field of research. Maybe Roddy's podcast? Maybe Resonant FM's podcast? Ray's extensive research and experience would greatly help Haidut in evaluating substances and could serve our community immensely.

@haidut @Dan Wich @Sucrates @#anyonewhocanhelpfacilitatethis

 

[Makrosky]

Just for the record, I don't see the OP's question as trying to discredit Haidut. Given the oracular-like type of dialogues that we normally have with Ray over the email it would have been wiser to ask the question in another more precise way BUT I don't see bad intentions. Call me naive?

I think it is not difficult to get too enthusiastic about haidut's new products and forgetting they are experimental. I would take this thread as a reminder of that. Such_S summarized it very good.

Another way to take it is... first try the well established routes (plain preg, dhea and progesterone) and leave the R&D for more serious things or if the previous ones do not help.

You are creating a problem where it shouldn't be one.

 

[lollipop]

@Makrosky I am assuming "you" means me in your above comment. Actually I am not trying to create a problem in any way. I am expressing a feeling I have albeit feelings are not always grounded in explicit data. Notice however, I did not remain there and complain complain complain. I attempted to move it to a new conscious solution that would bring benefit for everyone. Not sure why you are singling me out on this one. I love the conversation and would love to see it deepened actually.

 

[Makrosky]

@Makrosky I am assuming "you" means me in your above comment. Actually I am not trying to create a problem in any way. I am expressing a feeling I have albeit feelings are not always grounded in explicit data. Notice however, I did not remain there and complain complain complain. I attempted to move it to a new conscious solution that would bring benefit for everyone. Not sure why you are singling me out on this one. I love the conversation and would love to see it deepened actually.

LOL!! No Lisa, my comment was a generic one to anyone following that line (schultz, you and haidut himself) and for anyone else wanting to jump into that wagon in future comments. Nothing personal, my word on that. :)

 

[Sucrates]

I agree with this wholeheartedly! Interesting conversations and they also seem a bit like a move to discredit Haidut without a thorough full sided discussion about the topics. It would be fascinating to try and facilitate an actual recorded conversation between Haidut and Ray on these individual substances after each (Ray and Haidut) have been provided the full field of research. Maybe Roddy's podcast? Maybe Resonant FM's podcast? Ray's extensive research and experience would greatly help Haidut in evaluating substances and could serve our community immensely.

@haidut @Dan Wich @Sucrates @#anyonewhocanhelpfacilitatethis

Not for me thanks.

 

[Dan W]

Not for me thanks.

Same here, my sole contact with Peat is roughly one annual e-mail question

I think Danny mentioned somewhere that he hadn't heard back from Peat on his last contact about another podcast too.

I think it's a cool podcast idea, but it might be difficult to make it happen.

 

[lollipop]

Same here, my sole contact with Peat is roughly one annual e-mail question

I think Danny mentioned somewhere that he hadn't heard back from Peat on his last contact about another podcast too.

I think it's a cool podcast idea, but it might be difficult to make it happen.

Thanks @Dan Wich @Sucrates makes sense. Just an idea. Would love in depth conversation.

 

[haidut]

Thanks @Dan Wich @Sucrates makes sense. Just an idea. Would love in depth conversation.

I would love such a conversation too. If anybody knows how to make it happen I would love to participate. In the meantime, again, if someone is in touch with Peat please send him the studies I posted about 5a-DHP. That will save him a lot of time to dig them himself, but I am sure he will do his part of the digging too.
I also views it as experimental chemical, just as several people here mentioned. Maybe the initial experiment is with pregnenolone and progesterone, and if say the goal is raising allopregnanolone and there is no effect due to PFS or some other situation resultign in 5-AR deficiency, then 5a-DHP can be considered. Another option would be for the people who are thinking of using progesterone to lower estrogen and prolactin, which it is known to do. The animal studies seem to say that a dose of 2-3 times higher would be needed if regular progesterone is used, and that can be lead to anti-androgenic effects as Peat himself has said and hence the recommendation for males to use pregnenolone instead. So, if a lower dose is desired or there is no observed effect from progesterone then 5a-DHP again becomes another option. It is just another option, not a replacement. I am beginning to wonder if I had gone with allopregnanolone as I had originally planned all this controversy would have been avoided...

 

[raypeatclips]

@haidut @Dan Wich @lisaferraro The Peat phone has been called.

 

[goodandevil]

Just for the record, I don't see the OP's question as trying to discredit Haidut. Given the oracular-like type of dialogues that we normally have with Ray over the email it would have been wiser to ask the question in another more precise way BUT I don't see bad intentions. Call me naive?

I think it is not difficult to get too enthusiastic about haidut's new products and forgetting they are experimental. I would take this thread as a reminder of that. Such_S summarized it very good.

Another way to take it is... first try the well established routes (plain preg, dhea and progesterone) and leave the R&D for more serious things or if the previous ones do not help.

You are creating a problem where it shouldn't be one.

Yeah no bad intentions on my part at all. Maybe 5a-dhprogesterone will have benefits where other agents do not. I'm just saying be careful, especially with DMSO, because I and others have had bad reactions to it. I would love to see Haidut keep doing well and challenge the pharmecutical companies or lawrence livermore or whoever. People in the past have sought to obliterate haidut as a human being but that's not me. I do think people should be more cautious, especially regarding the DMSO, and I think that's the main point ray is trying to get across: caution. Plus he abandoned DMSO. These other agents besides DMSO certainly have potential and somebody has to experiment with them, but experimenting means remaining sensitive and cautious to side effects, that should always be remembered. Look at how many people take fish oil and swear by it. Is my man Haidut selling fish oil? No. But it illustrates the power of belief. If you already believe in a compound it's no experiment.

 

[raypeatclips]

@haidut Ray has replied to the email about potentially talking with you about the hormones mentioned.

"I don’t know anything that would make me want to consider their use as supplements.


J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):166-76.
Mechanism of action of the breast cancer-promoter hormone, 5α-dihydroprogesterone
(5αP), involves plasma membrane-associated receptors and MAPK activation.
Wiebe JP(1), Pawlak KJ(2), Kwok A(3).
(1)Department of Biology, The University of Western Ontario, London, ON N6A 5B7,
Canada. Electronic address: [email protected]. (2)Department of Physiology, School of
Medicine, Zirve University, Gaziantep, Turkey. (3)Department of Biology, The
University of Western Ontario, London, ON N6A 5B7, Canada.
Previous studies have shown that breast tissues and breast cell lines can convert
progesterone to 5α-pregnane-3,20-dione (5aP), and that 5αP stimulates breast cell
proliferation and detachment in vitro, and tumor formation in vivo, regardless of
presence or absence of receptors for progesterone (PR) or estrogen (ER). Recently
it was demonstrated, both in vitro and in vivo, that pro-cancer actions
attributed to administered progesterone are due to the in situ produced 5αP.
Because of the significant role of 5αP in breast cancers, it is important to
understand its molecular mechanisms of action. The aims of the current studies
were to identify 5αP binding sites and to determine if the mechanisms of action
of 5αP involve the mitogen-activated protein kinase (MAPK), extracellular
signal-regulated protein kinases (ERK1/2) pathway. Binding studies, using
tritium-labeled 5αP ([(3)H]5αP), carried out on membrane, cytosol and nuclear
fractions from human breast cells (MCF-7, PR/ER-positive; MDA-MB-231,
PR/ER-negative) and on highly enriched membrane fractions, identified the plasma
membrane as the site of ligand specific 5αP receptors. Localization of 5αP
receptors to the cell membrane was confirmed visually with fluorescently labeled
conjugate (5αP-BSA-FITC). Treatment of cells with either 5αP or
membrane-impermeable 5αP-BSA resulted in significant increases in cell
proliferation and detachment. 5αP and 5αP-BSA equally activated the MAPK/ERK1/2
pathway as evidenced by phosphorylation of ERK1/2. Inhibitors (PD98059,
mevastatin and genistein) of specific sites along the Ras/Raf/MEK/ERK signaling
pathway, blocked the phosphorylation and concomitantly inhibited 5αP-induced
stimulation of cell proliferation and detachment. The study has identified high
affinity, stereo-specific binding sites for 5αP that have the characteristics of
a functional membrane 5αP receptor, and has shown that the cancer-promoter
actions of 5αP are mediated from the liganded receptor via the MAPK/ERK1/2
signaling cascade. The findings enhance our understanding of the role of the
progesterone metabolite 5αP in breast cancer and should promote new approaches to
the development of breast cancer diagnostics and therapeutics.

Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11.
Distinct molecular pathways mediate progesterone-induced growth inhibition and
focal adhesion.
Lin VC(1), Woon CT, Aw SE, Guo C.
(1)Department of Clinical Research, Singapore General Hospital, School of
Biological Sciences, School, Singapore 637616. [email protected].
We have reported previously that reactivation of progesterone receptor (PR)
expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer
cells enabled progesterone to inhibit cell growth and invasiveness, and to induce
remarkable focal adhesions. The present study addressed molecular mechanisms that
mediate these anticancer effects of progesterone in the PR-transfected breast
cancer cells ABC28. In response to progesterone treatment are the marked
up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and
decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for
G1 progression and during cell mitosis. Progesterone also induced down-regulation
of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated
that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also
caused reduction of cyclin D1 level and inhibition of cell proliferation. These
results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms
mediating progesterone's growth-inhibitory effect. On the other hand,
progesterone-induced focal adhesion is mediated by separate pathway. Whereas
PD98059 exhibited no effects on cell adhesion, inhibitory antibody to
beta1-integrin was able to reverse progesterone-induced focal adhesion and
progesterone-induced increase in the phosphorylation of focal adhesion kinase. On
the other hand, beta1-integrin antibody had no effect on progesterone-mediated
growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1
and phosphorylation of P42/P44 MAPK. In the context of complex functions of
progesterone in breast cancer and reproductive organs, identification of distinct
pathways offers new strategies for designing therapeutic agents to target the
specific pathway so as to minimize the side effects.

J Steroid Biochem Mol Biol. 2005 Nov;97(3):278-88.
Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A
breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated
by the progesterone metabolites, 3alpha-dihydroprogesterone and
20alpha-dihydroprogesterone, with associated changes in cell proliferation and
detachment.
Pawlak KJ(1), Zhang G, Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, Department of Biology, University
of Western Ontario, London, Canada.
Previous studies have shown that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity
in breast cell lines and that specific, high affinity receptors for 5alphaP are
located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7
cells. The aim of this study was to determine the effects of the mitogenic
(estradiol; 5alphaP) and anti-mitogenic (3alpha-hydroxy-4-pregnen-20-one,
3alphaHP; 20alpha-hydroxy-4-pregnen-3-one, 20alphaHP) endogenous steroid hormones
on 5alphaP receptor (5alphaP-R) numbers and on cell proliferation and adhesion of
MCF-7 and MCF-10A cells. Exposure of MCF-7 cells for 24h to estradiol or 5alphaP
resulted in significant (p < 0.05-0.001) dose-dependent increases in 5alphaP-R
levels. Conversely, treatment with 3alphaHP or 20alphaHP resulted in significant
(p < 0.05-0.01) dose-dependent decreases in 5alphaP-R levels. Treatment with one
mitogenic and one anti-mitogenic hormone resulted in inhibition of the
mitogen-induced increases, whereas treatment with two mitogenic or two
anti-mitogenic hormones resulted in additive effects on 5alphaP-R numbers.
Treatments with cycloheximide and actinomycin D indicate that changes in
5alphaP-R levels depend upon transcription and translation. The non-tumorigenic
breast cell line, MCF-10A, was also shown to posses specific, high affinity
plasma membrane receptors for 5alphaP that were up-regulated by estradiol and
5alphaP and down-regulated by 3alphaHP. Estradiol binding was demonstrated in
MCF-10A cell membrane fractions and may explain the estradiol action in these
cells that lack intracellular ER. In both MCF-7 and MCF-10A cells, the increases
in 5alphaP-R due to estradiol or 5alphaP, and decreases due to 3alphaHP or
20alphaHP correlate with respective increases and decreases in cell proliferation
as well as detachment. These results show distribution of 5alphaP-R in several
cell types and they provide further evidence of the significance of progesterone
metabolites and their novel membrane-associated receptors in breast cancer
stimulation and control. The findings that 3alphaHP and 20alphaHP down-regulate
5alphaP-R and suppress mitogenic and metastatic activity suggest that these
endogenous anti-mitogenic progesterone metabolites deserve considerations in
designing new breast cancer therapeutic agents.

Biochem Biophys Res Commun. 2000 Jun 16;272(3):731-7.

Plasma membrane receptors for the cancer-regulating progesterone metabolites,
5alpha-pregnane-3,20-dione and 3alpha-hydroxy-4-pregnen-20-one in MCF-7 breast
cancer cells.
Weiler PJ(1), Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario,
London, Canada.
Recent observations indicate that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), which is produced at higher levels in
tumorous breast tissue, promotes cell proliferation and detachment, whereas
3alpha-hydroxy-4-pregnen-20-one (3alphaHP), which is produced at higher levels in
nontumorous breast tissue, suppresses proliferation and detachment of MCF-7
breast cancer cells. The objective of the current study was to determine the
presence and characteristics of binding sites for these endogenous putative
cancer-regulating steroid hormones. Radiolabeled 5alphaP and 3alphaHP were used
in radioligand binding assays on MCF-7 cell (membrane, cytosolic, and nuclear)
fractions. Binding of [(3)H]5alphaP and [(3)H]3alphaHP was observed only in the
plasma membrane fraction, whereas estradiol binding sites were confirmed in the
cytosolic and nuclear fractions. The respective membrane binding sites exhibited
specificity for the 5alphaP and 3alphaHP ligands with no appreciable displacement
at 200- to 500-fold excess by other steroids. The association rate constants were
calculated as 0. 107/min and 0.0089/min and the dissociation rate constants were
0. 049 9 and 0.011 for 5alphaP and 3alphaHP, respectively. Saturation analyses
indicated single classes of molecules with dissociation constants of 4.5 and 4.87
nM and receptor densities of 486 and 629 fmol/mg protein, respectively, for
5alphaP and 3alphaHP. Exposure of MCF-7 cells to estradiol for 1, 24, 48, and 72
h resulted in 2.3, 4. 2-, 2.99-, and 1.7-fold increases, respectively, in 5alphaP
receptor density. 3alphaHP resulted in partial suppression of the
estradiol-mediated increase in 5alphaP receptor density. This is the first report
of receptors for the progesterone metabolites, 5alphaP and 3alphaHP, of their
occurrence in breast cancer cell membranes, and of the induction of 5alphaP
receptors by estradiol. The results provide further support for the potential
importance of progesterone metabolites in breast cancer.
Copyright 2000 Academic Press.

Breast Cancer Res. 2013 May 11;15(3):R38.
Progesterone metabolites regulate induction, growth, and suppression of estrogen-
and progesterone receptor-negative human breast cell tumors.
Wiebe JP(1), Zhang G(2,)(3), Welch I(4), Cadieux-Pitre HA(5).
(1)Department of Biology, The University of Western Ontario, London, Ontario,
N6A5B7, Canada. [email protected] (2)Department of Biology, The University of Western
Ontario, London, Ontario, N6A5B7, Canada. [email protected].
(3)Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected]. (4)Department of Animal Care & Veterinary Services
and Department of Physiology and Pharmacology, Medical Sciences Building, The
University of Western Ontario, London, Ontario, N6A 5C1, Canada. [email protected].
(5)Department of Animal Care & Veterinary Services, Medical Sciences Building,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected].
INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each
year, a large proportion is characterized as hormone receptor negative, lacking
estrogen receptors (ER) and/or progesterone receptors (PR). Patients with
receptor-negative tumors do not respond to current steroid hormone-based
therapies and generally have significantly higher risk of recurrence and
mortality compared with patients with tumors that are ER- and/or PR-positive.
Previous in vitro studies had shown that the progesterone metabolites,
5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively,
exhibit procancer and anticancer effects on receptor-negative human breast cell
lines. Here in vivo studies were conducted to investigate the ability of 5αP and
3αHP to control initiation, growth, and regression of ER/PR-negative human breast
cell tumors.
METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into
mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP
treatments on tumor initiation, growth, suppression/regression, and
histopathology were assessed in five separate experiments. Specific
radioimmunoassays and gas chromatography-mass spectrometry were used to measure
5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were
significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were
applied simultaneously, the stimulatory effects of 5αP were abrogated by the
inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to
5αP-induced tumor initiation resulted in suppression of further tumorigenesis and
regression of existing tumors. The levels of 5αP in tumors, regardless of
treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP
ratios were about fivefold higher than in serum, indicating significant changes
in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast
tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and
3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by
5αP and suppressed by 3αHP, the outcome depending on the relative concentrations
of these two hormones in the microenvironment in the breast regions. The findings
show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative
tumors and that treatment with 3αHP can effectively block tumorigenesis and cause
existing tumors to regress. The results provide the first hormonal theory to
explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis
that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster
normalcy in noncancerous breast regions. The findings suggest new diagnostics
based on the relative levels of these hormones and new approaches to prevention
and treatment of breast cancers based on regulating the levels and action
mechanisms of anti- and pro-cancer progesterone metabolites."

 

[haidut]

@haidut Ray has replied to the email about potentially talking with you about the hormones mentioned.

"I don’t know anything that would make me want to consider their use as supplements.


J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):166-76.
Mechanism of action of the breast cancer-promoter hormone, 5α-dihydroprogesterone
(5αP), involves plasma membrane-associated receptors and MAPK activation.
Wiebe JP(1), Pawlak KJ(2), Kwok A(3).
(1)Department of Biology, The University of Western Ontario, London, ON N6A 5B7,
Canada. Electronic address: [email protected]. (2)Department of Physiology, School of
Medicine, Zirve University, Gaziantep, Turkey. (3)Department of Biology, The
University of Western Ontario, London, ON N6A 5B7, Canada.
Previous studies have shown that breast tissues and breast cell lines can convert
progesterone to 5α-pregnane-3,20-dione (5aP), and that 5αP stimulates breast cell
proliferation and detachment in vitro, and tumor formation in vivo, regardless of
presence or absence of receptors for progesterone (PR) or estrogen (ER). Recently
it was demonstrated, both in vitro and in vivo, that pro-cancer actions
attributed to administered progesterone are due to the in situ produced 5αP.
Because of the significant role of 5αP in breast cancers, it is important to
understand its molecular mechanisms of action. The aims of the current studies
were to identify 5αP binding sites and to determine if the mechanisms of action
of 5αP involve the mitogen-activated protein kinase (MAPK), extracellular
signal-regulated protein kinases (ERK1/2) pathway. Binding studies, using
tritium-labeled 5αP ([(3)H]5αP), carried out on membrane, cytosol and nuclear
fractions from human breast cells (MCF-7, PR/ER-positive; MDA-MB-231,
PR/ER-negative) and on highly enriched membrane fractions, identified the plasma
membrane as the site of ligand specific 5αP receptors. Localization of 5αP
receptors to the cell membrane was confirmed visually with fluorescently labeled
conjugate (5αP-BSA-FITC). Treatment of cells with either 5αP or
membrane-impermeable 5αP-BSA resulted in significant increases in cell
proliferation and detachment. 5αP and 5αP-BSA equally activated the MAPK/ERK1/2
pathway as evidenced by phosphorylation of ERK1/2. Inhibitors (PD98059,
mevastatin and genistein) of specific sites along the Ras/Raf/MEK/ERK signaling
pathway, blocked the phosphorylation and concomitantly inhibited 5αP-induced
stimulation of cell proliferation and detachment. The study has identified high
affinity, stereo-specific binding sites for 5αP that have the characteristics of
a functional membrane 5αP receptor, and has shown that the cancer-promoter
actions of 5αP are mediated from the liganded receptor via the MAPK/ERK1/2
signaling cascade. The findings enhance our understanding of the role of the
progesterone metabolite 5αP in breast cancer and should promote new approaches to
the development of breast cancer diagnostics and therapeutics.

Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11.
Distinct molecular pathways mediate progesterone-induced growth inhibition and
focal adhesion.
Lin VC(1), Woon CT, Aw SE, Guo C.
(1)Department of Clinical Research, Singapore General Hospital, School of
Biological Sciences, School, Singapore 637616. [email protected].
We have reported previously that reactivation of progesterone receptor (PR)
expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer
cells enabled progesterone to inhibit cell growth and invasiveness, and to induce
remarkable focal adhesions. The present study addressed molecular mechanisms that
mediate these anticancer effects of progesterone in the PR-transfected breast
cancer cells ABC28. In response to progesterone treatment are the marked
up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and
decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for
G1 progression and during cell mitosis. Progesterone also induced down-regulation
of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated
that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also
caused reduction of cyclin D1 level and inhibition of cell proliferation. These
results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms
mediating progesterone's growth-inhibitory effect. On the other hand,
progesterone-induced focal adhesion is mediated by separate pathway. Whereas
PD98059 exhibited no effects on cell adhesion, inhibitory antibody to
beta1-integrin was able to reverse progesterone-induced focal adhesion and
progesterone-induced increase in the phosphorylation of focal adhesion kinase. On
the other hand, beta1-integrin antibody had no effect on progesterone-mediated
growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1
and phosphorylation of P42/P44 MAPK. In the context of complex functions of
progesterone in breast cancer and reproductive organs, identification of distinct
pathways offers new strategies for designing therapeutic agents to target the
specific pathway so as to minimize the side effects.

J Steroid Biochem Mol Biol. 2005 Nov;97(3):278-88.
Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A
breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated
by the progesterone metabolites, 3alpha-dihydroprogesterone and
20alpha-dihydroprogesterone, with associated changes in cell proliferation and
detachment.
Pawlak KJ(1), Zhang G, Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, Department of Biology, University
of Western Ontario, London, Canada.
Previous studies have shown that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity
in breast cell lines and that specific, high affinity receptors for 5alphaP are
located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7
cells. The aim of this study was to determine the effects of the mitogenic
(estradiol; 5alphaP) and anti-mitogenic (3alpha-hydroxy-4-pregnen-20-one,
3alphaHP; 20alpha-hydroxy-4-pregnen-3-one, 20alphaHP) endogenous steroid hormones
on 5alphaP receptor (5alphaP-R) numbers and on cell proliferation and adhesion of
MCF-7 and MCF-10A cells. Exposure of MCF-7 cells for 24h to estradiol or 5alphaP
resulted in significant (p < 0.05-0.001) dose-dependent increases in 5alphaP-R
levels. Conversely, treatment with 3alphaHP or 20alphaHP resulted in significant
(p < 0.05-0.01) dose-dependent decreases in 5alphaP-R levels. Treatment with one
mitogenic and one anti-mitogenic hormone resulted in inhibition of the
mitogen-induced increases, whereas treatment with two mitogenic or two
anti-mitogenic hormones resulted in additive effects on 5alphaP-R numbers.
Treatments with cycloheximide and actinomycin D indicate that changes in
5alphaP-R levels depend upon transcription and translation. The non-tumorigenic
breast cell line, MCF-10A, was also shown to posses specific, high affinity
plasma membrane receptors for 5alphaP that were up-regulated by estradiol and
5alphaP and down-regulated by 3alphaHP. Estradiol binding was demonstrated in
MCF-10A cell membrane fractions and may explain the estradiol action in these
cells that lack intracellular ER. In both MCF-7 and MCF-10A cells, the increases
in 5alphaP-R due to estradiol or 5alphaP, and decreases due to 3alphaHP or
20alphaHP correlate with respective increases and decreases in cell proliferation
as well as detachment. These results show distribution of 5alphaP-R in several
cell types and they provide further evidence of the significance of progesterone
metabolites and their novel membrane-associated receptors in breast cancer
stimulation and control. The findings that 3alphaHP and 20alphaHP down-regulate
5alphaP-R and suppress mitogenic and metastatic activity suggest that these
endogenous anti-mitogenic progesterone metabolites deserve considerations in
designing new breast cancer therapeutic agents.

Biochem Biophys Res Commun. 2000 Jun 16;272(3):731-7.

Plasma membrane receptors for the cancer-regulating progesterone metabolites,
5alpha-pregnane-3,20-dione and 3alpha-hydroxy-4-pregnen-20-one in MCF-7 breast
cancer cells.
Weiler PJ(1), Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario,
London, Canada.
Recent observations indicate that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), which is produced at higher levels in
tumorous breast tissue, promotes cell proliferation and detachment, whereas
3alpha-hydroxy-4-pregnen-20-one (3alphaHP), which is produced at higher levels in
nontumorous breast tissue, suppresses proliferation and detachment of MCF-7
breast cancer cells. The objective of the current study was to determine the
presence and characteristics of binding sites for these endogenous putative
cancer-regulating steroid hormones. Radiolabeled 5alphaP and 3alphaHP were used
in radioligand binding assays on MCF-7 cell (membrane, cytosolic, and nuclear)
fractions. Binding of [(3)H]5alphaP and [(3)H]3alphaHP was observed only in the
plasma membrane fraction, whereas estradiol binding sites were confirmed in the
cytosolic and nuclear fractions. The respective membrane binding sites exhibited
specificity for the 5alphaP and 3alphaHP ligands with no appreciable displacement
at 200- to 500-fold excess by other steroids. The association rate constants were
calculated as 0. 107/min and 0.0089/min and the dissociation rate constants were
0. 049 9 and 0.011 for 5alphaP and 3alphaHP, respectively. Saturation analyses
indicated single classes of molecules with dissociation constants of 4.5 and 4.87
nM and receptor densities of 486 and 629 fmol/mg protein, respectively, for
5alphaP and 3alphaHP. Exposure of MCF-7 cells to estradiol for 1, 24, 48, and 72
h resulted in 2.3, 4. 2-, 2.99-, and 1.7-fold increases, respectively, in 5alphaP
receptor density. 3alphaHP resulted in partial suppression of the
estradiol-mediated increase in 5alphaP receptor density. This is the first report
of receptors for the progesterone metabolites, 5alphaP and 3alphaHP, of their
occurrence in breast cancer cell membranes, and of the induction of 5alphaP
receptors by estradiol. The results provide further support for the potential
importance of progesterone metabolites in breast cancer.
Copyright 2000 Academic Press.

Breast Cancer Res. 2013 May 11;15(3):R38.
Progesterone metabolites regulate induction, growth, and suppression of estrogen-
and progesterone receptor-negative human breast cell tumors.
Wiebe JP(1), Zhang G(2,)(3), Welch I(4), Cadieux-Pitre HA(5).
(1)Department of Biology, The University of Western Ontario, London, Ontario,
N6A5B7, Canada. [email protected] (2)Department of Biology, The University of Western
Ontario, London, Ontario, N6A5B7, Canada. [email protected].
(3)Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected]. (4)Department of Animal Care & Veterinary Services
and Department of Physiology and Pharmacology, Medical Sciences Building, The
University of Western Ontario, London, Ontario, N6A 5C1, Canada. [email protected].
(5)Department of Animal Care & Veterinary Services, Medical Sciences Building,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected].
INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each
year, a large proportion is characterized as hormone receptor negative, lacking
estrogen receptors (ER) and/or progesterone receptors (PR). Patients with
receptor-negative tumors do not respond to current steroid hormone-based
therapies and generally have significantly higher risk of recurrence and
mortality compared with patients with tumors that are ER- and/or PR-positive.
Previous in vitro studies had shown that the progesterone metabolites,
5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively,
exhibit procancer and anticancer effects on receptor-negative human breast cell
lines. Here in vivo studies were conducted to investigate the ability of 5αP and
3αHP to control initiation, growth, and regression of ER/PR-negative human breast
cell tumors.
METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into
mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP
treatments on tumor initiation, growth, suppression/regression, and
histopathology were assessed in five separate experiments. Specific
radioimmunoassays and gas chromatography-mass spectrometry were used to measure
5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were
significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were
applied simultaneously, the stimulatory effects of 5αP were abrogated by the
inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to
5αP-induced tumor initiation resulted in suppression of further tumorigenesis and
regression of existing tumors. The levels of 5αP in tumors, regardless of
treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP
ratios were about fivefold higher than in serum, indicating significant changes
in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast
tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and
3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by
5αP and suppressed by 3αHP, the outcome depending on the relative concentrations
of these two hormones in the microenvironment in the breast regions. The findings
show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative
tumors and that treatment with 3αHP can effectively block tumorigenesis and cause
existing tumors to regress. The results provide the first hormonal theory to
explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis
that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster
normalcy in noncancerous breast regions. The findings suggest new diagnostics
based on the relative levels of these hormones and new approaches to prevention
and treatment of breast cancers based on regulating the levels and action
mechanisms of anti- and pro-cancer progesterone metabolites."

Thanks. I did see those studies. I have emailed the authors of the above studies as I suspect this effect is a fluke or due to specific cell lines. A chemical with such strong inhibition of estrogen and prolactin should now have these effects. Please send him these two studies:

1. Prolactin inhibition: https://www.ncbi.nlm.nih.gov/pubmed/19215357

"...The purpose of this study was to examine whether the effect of different doses of progesterone on estrogen-induced prolactin release correlated with the effects of progesterone on estrogen receptor dynamics of the anterior pituitary demonstrated by Fuentes et al. (13). In our study, the 0.8 mg/kg body wt and 3.2 mg/kg body wt doses of progesterone inhibited estrogen-induced prolactin release (64% and 60% reduction) whereas the 2.0mg/kg body wt dose was ineffective (4% reduction)."

"...In view of the uniqueness of this observation it was important to confirm that two doses of the same steroid were active in bringing about a biological change while the intermediate dose was either ineffective or minimally effective. For this purpose we sought out another steroid 5a-dihydroprogesterone, which was related to progesterone and interacted with the progesterone receptor. It also was reported to bring about the selective release of follicle-stimulating hormone by Murphy and Mahesh (15). Progesterone is actively metabolized by both the hypothalamus and anterior pituitary to various metabolites, principally 5adihydroprogesterone (14). 5a-dihydroprogesterone has been shown to bind with high affinity to the progesterone receptor in a variety of tissues (21 -23). In this study 5a-dihydroprogesterone was found to inhibit estrogen-induced prolactin release similar to progesterone (Fig. 2)."

"...The effect of 5a-dihydroprogesterone upon estradiol-induced prolactin release was influenced by the dose used (Fig. 2). Similar to progesterone, Sa-dihydroprogesterone caused a decrease or no effect on pituitary nuclear estradiol receptors depending upon the dose used (24). A strong correlation was found between those doses which depleted pituitary-occupied nuclear estrogen receptors in the Fuentes et al. study (13) and those that inhibited estradiol-induced prolactin release in this study. In the study of Fuentes et al. (24), the 0.2 mg/kg body wt and 2.0 mg/kg body wt doses of 5α-dihydroprogesterone were more effective in reducing occupied pituitary estrogen receptor levels (54% and 74% reduction; P < 0.01 for both groups) as compared to the 0.8 mg/kg body wt dose (31% reduction) in which the reduction was not significant. In our study, the 0.4 mg/kg body wt and 2.0 mg/kg body wt doses of 5α-dihydroprogesterone inhibited estrogen-induced prolactin release (68% reduction for each), whereas the 0.8 mg/kg body wt dose was ineffective (17% reduction)."

"...Of considerable interest is the finding that 5α-dihydroprogesterone is twice as potent as progesterone with respect to its effect upon both the estrogen receptor depletion (24) and inhibition of estrogen-induced prolactin secretion (compare Fig. 1 vs Fig. 2). Murphy and Mahesh also reported that the 0.4 mg/kg body wt dose of 5α-dihydroprogesterone brought about selective release of follicle-stimulating hormone in ovariectomized estrogen-primed immature rats (15) and adult rats ovariectomized on the day of proestrus (19), while the 0.8 mg/kg body wt dose was ineffective. The higher potency of 5α-dihydroprogesterone compared to progesterone may suggest a critical role for 5α-dihydroprogesterone as an active mediator of progesterone action at the level of the anterior pituitary."


2. Estrogen inhibition: Inhibitory effect of 5-alpha-dihydroprogesterone on nuclear estrogen receptor binding of the anterior pituitary and uterus in the rat. - PubMed - NCBI

"...Treatment with estradiol appeared to bring about an increase in both total and occupied nuclear E2R binding and different doses of 5α-DHP appeared to decrease the total and occupied E2R binding by varying degrees. Using a similar experimental design and esperession of results, figure 2 shows the changes in nuclear E2R binding activity in the uterus where 5α-DHP also decreased total and occupied E2R binding. In view of the large number of animals needed for detailed studies which required at least 3 replicates for statistical analysis, the doses of 0.2, 0.8, and 2.0 mg/kg BW of 5α-DHP were chosen for further study. Table 1 shows the pituitary nuclear E2R-binding after various treatments. Total nuclear E2R levels showed a 2-fold increase in all experiments in the estradiol-treated group as compared to the vehicle-treated controls (table 1). When 5α-DHP was injected in estrogen-primed ovariectomized rats 1h before the final estrogen injection, it decreased the nuclear accumulation of E2Rs in the anterior pituitary, the decrease being greater with the 0.2- and 2mg/kg BW doses as compared to the 0.8mg/kg BW dose of 5α-DHP. In the present study we observed that the acute administration of 5α-DHP to estrogen-primed rats was able to antagonize the estrogen-induced increase in nuclear E2Rs in a tissue-specific manner. The response in the anterior pituitary followed a multiphasic pattern of decrease in occupied E2Rs. The 0.2 and 2.0mg/kg BW doses of 5α-DHP were effective in decreasing the nuclear E2R binding. The patterns of change in nuclear E2R examined in response to estradiol and 5α-DHP were similar in all experiments. However, there were considerable differences in the level E2Rs found in different experiments. We [18, 27] and others [28] had observed seasonal changes in E2Rs previously, the explanation for which was unclear. In view of these differences, the results in figures 3 and 5 were calculated on percentage change within each experiment. In the uterus, 5α-DHP-induced decreases in total E2R levels also occurred in occupied nuclear E2R level. The pattern of change, however, was remarkably different from that found in the anterior pituitary. The effect of 5α-DHP on the occupied uterine nuclear E2Rs was a dose-dependent decrease with no multiphasic variations.

"...It has been shown that 5α-DHP binds almost as well as progesterone to the progesterone receptor in the pituitary [29] and hypothalamus of the rat [30], oviduct of estrogen-primed chicks [31] and guinea pig uterus [32]. The involvement of the progesterone receptor system in 5α-DHP action was addressed in experiments with the antiprogestin RU486 that showed antagonism of the 5α-DHP-induced decrease in prolactin release in estrogen-primed immature rats. An interesting finding was the observation that the multiphasic effect of 5α-DHP on anterior pituitary nuclear E2R was similar to the previously reported multiphasic effect of progesterone in the same animal model [20]. Progesterone doses of 0.8, 2 and 4 mg/kg BW give occupied nuclear E2R levels of 35%, 66% and 28% of the occupied level observed in the estradiol control group (100% occupied E2Rs), respectively. The levels of occupied nuclear E2Rs with the 0.2, 0.8 adn 2mg/kg BW doses of 5α-DHP were 50%, 72%, and 25%, respectively, of the level in the estrogen control group (100%). Thus, the doses of 5α-DHP necessary to induce similar decreased in E2R levels are generally lower than those of progesterone."

Now, here is the million dollar question that goes way beyond my chemical. This study below by the same authors publishing the studies Ray sent, claims that progesterone CAN stimulate breast cancer growth through the metabolism into 5a-DHP. Administering finasteride blocked that stimulating effect.
Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed... - PubMed - NCBI

So, does that mean that progesterone can actually be dangerous, especially for breast cancer conditions, unless administered with a 5-AR inhibitor like finasteride? If that is true, then what is the context under which the article below on progesterone as breast (and other) cancer treatment should be interpreted?
Preventing and treating cancer with progesterone.

If progesterone can be dangerous for the very condition that it is supposed to treat, then what other conditions is it potentially dangerous for? Keeping in mind that in most people a good portion of progesterone will metabolize into allopregnanolone and as such will have to elevate 5a-DHP levels as well, unless finasteride is taken.
Allopregnanolone - Wikipedia
"...This seems to be a common effect of many GABAA receptor positive allosteric modulators.[25][30] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect."

I am just asking these questions out of pure curiosity, not trying to be confrontational in any way. Progesterone is one of the cornerstones of metabolic therapy, so (at least to me) it is very important to get some clarity on this.

 

[haidut]

@haidut Ray has replied to the email about potentially talking with you about the hormones mentioned.

"I don’t know anything that would make me want to consider their use as supplements.


J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):166-76.
Mechanism of action of the breast cancer-promoter hormone, 5α-dihydroprogesterone
(5αP), involves plasma membrane-associated receptors and MAPK activation.
Wiebe JP(1), Pawlak KJ(2), Kwok A(3).
(1)Department of Biology, The University of Western Ontario, London, ON N6A 5B7,
Canada. Electronic address: [email protected]. (2)Department of Physiology, School of
Medicine, Zirve University, Gaziantep, Turkey. (3)Department of Biology, The
University of Western Ontario, London, ON N6A 5B7, Canada.
Previous studies have shown that breast tissues and breast cell lines can convert
progesterone to 5α-pregnane-3,20-dione (5aP), and that 5αP stimulates breast cell
proliferation and detachment in vitro, and tumor formation in vivo, regardless of
presence or absence of receptors for progesterone (PR) or estrogen (ER). Recently
it was demonstrated, both in vitro and in vivo, that pro-cancer actions
attributed to administered progesterone are due to the in situ produced 5αP.
Because of the significant role of 5αP in breast cancers, it is important to
understand its molecular mechanisms of action. The aims of the current studies
were to identify 5αP binding sites and to determine if the mechanisms of action
of 5αP involve the mitogen-activated protein kinase (MAPK), extracellular
signal-regulated protein kinases (ERK1/2) pathway. Binding studies, using
tritium-labeled 5αP ([(3)H]5αP), carried out on membrane, cytosol and nuclear
fractions from human breast cells (MCF-7, PR/ER-positive; MDA-MB-231,
PR/ER-negative) and on highly enriched membrane fractions, identified the plasma
membrane as the site of ligand specific 5αP receptors. Localization of 5αP
receptors to the cell membrane was confirmed visually with fluorescently labeled
conjugate (5αP-BSA-FITC). Treatment of cells with either 5αP or
membrane-impermeable 5αP-BSA resulted in significant increases in cell
proliferation and detachment. 5αP and 5αP-BSA equally activated the MAPK/ERK1/2
pathway as evidenced by phosphorylation of ERK1/2. Inhibitors (PD98059,
mevastatin and genistein) of specific sites along the Ras/Raf/MEK/ERK signaling
pathway, blocked the phosphorylation and concomitantly inhibited 5αP-induced
stimulation of cell proliferation and detachment. The study has identified high
affinity, stereo-specific binding sites for 5αP that have the characteristics of
a functional membrane 5αP receptor, and has shown that the cancer-promoter
actions of 5αP are mediated from the liganded receptor via the MAPK/ERK1/2
signaling cascade. The findings enhance our understanding of the role of the
progesterone metabolite 5αP in breast cancer and should promote new approaches to
the development of breast cancer diagnostics and therapeutics.

Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11.
Distinct molecular pathways mediate progesterone-induced growth inhibition and
focal adhesion.
Lin VC(1), Woon CT, Aw SE, Guo C.
(1)Department of Clinical Research, Singapore General Hospital, School of
Biological Sciences, School, Singapore 637616. [email protected].
We have reported previously that reactivation of progesterone receptor (PR)
expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer
cells enabled progesterone to inhibit cell growth and invasiveness, and to induce
remarkable focal adhesions. The present study addressed molecular mechanisms that
mediate these anticancer effects of progesterone in the PR-transfected breast
cancer cells ABC28. In response to progesterone treatment are the marked
up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and
decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for
G1 progression and during cell mitosis. Progesterone also induced down-regulation
of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated
that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also
caused reduction of cyclin D1 level and inhibition of cell proliferation. These
results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms
mediating progesterone's growth-inhibitory effect. On the other hand,
progesterone-induced focal adhesion is mediated by separate pathway. Whereas
PD98059 exhibited no effects on cell adhesion, inhibitory antibody to
beta1-integrin was able to reverse progesterone-induced focal adhesion and
progesterone-induced increase in the phosphorylation of focal adhesion kinase. On
the other hand, beta1-integrin antibody had no effect on progesterone-mediated
growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1
and phosphorylation of P42/P44 MAPK. In the context of complex functions of
progesterone in breast cancer and reproductive organs, identification of distinct
pathways offers new strategies for designing therapeutic agents to target the
specific pathway so as to minimize the side effects.

J Steroid Biochem Mol Biol. 2005 Nov;97(3):278-88.
Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A
breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated
by the progesterone metabolites, 3alpha-dihydroprogesterone and
20alpha-dihydroprogesterone, with associated changes in cell proliferation and
detachment.
Pawlak KJ(1), Zhang G, Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, Department of Biology, University
of Western Ontario, London, Canada.
Previous studies have shown that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity
in breast cell lines and that specific, high affinity receptors for 5alphaP are
located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7
cells. The aim of this study was to determine the effects of the mitogenic
(estradiol; 5alphaP) and anti-mitogenic (3alpha-hydroxy-4-pregnen-20-one,
3alphaHP; 20alpha-hydroxy-4-pregnen-3-one, 20alphaHP) endogenous steroid hormones
on 5alphaP receptor (5alphaP-R) numbers and on cell proliferation and adhesion of
MCF-7 and MCF-10A cells. Exposure of MCF-7 cells for 24h to estradiol or 5alphaP
resulted in significant (p < 0.05-0.001) dose-dependent increases in 5alphaP-R
levels. Conversely, treatment with 3alphaHP or 20alphaHP resulted in significant
(p < 0.05-0.01) dose-dependent decreases in 5alphaP-R levels. Treatment with one
mitogenic and one anti-mitogenic hormone resulted in inhibition of the
mitogen-induced increases, whereas treatment with two mitogenic or two
anti-mitogenic hormones resulted in additive effects on 5alphaP-R numbers.
Treatments with cycloheximide and actinomycin D indicate that changes in
5alphaP-R levels depend upon transcription and translation. The non-tumorigenic
breast cell line, MCF-10A, was also shown to posses specific, high affinity
plasma membrane receptors for 5alphaP that were up-regulated by estradiol and
5alphaP and down-regulated by 3alphaHP. Estradiol binding was demonstrated in
MCF-10A cell membrane fractions and may explain the estradiol action in these
cells that lack intracellular ER. In both MCF-7 and MCF-10A cells, the increases
in 5alphaP-R due to estradiol or 5alphaP, and decreases due to 3alphaHP or
20alphaHP correlate with respective increases and decreases in cell proliferation
as well as detachment. These results show distribution of 5alphaP-R in several
cell types and they provide further evidence of the significance of progesterone
metabolites and their novel membrane-associated receptors in breast cancer
stimulation and control. The findings that 3alphaHP and 20alphaHP down-regulate
5alphaP-R and suppress mitogenic and metastatic activity suggest that these
endogenous anti-mitogenic progesterone metabolites deserve considerations in
designing new breast cancer therapeutic agents.

Biochem Biophys Res Commun. 2000 Jun 16;272(3):731-7.

Plasma membrane receptors for the cancer-regulating progesterone metabolites,
5alpha-pregnane-3,20-dione and 3alpha-hydroxy-4-pregnen-20-one in MCF-7 breast
cancer cells.
Weiler PJ(1), Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario,
London, Canada.
Recent observations indicate that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), which is produced at higher levels in
tumorous breast tissue, promotes cell proliferation and detachment, whereas
3alpha-hydroxy-4-pregnen-20-one (3alphaHP), which is produced at higher levels in
nontumorous breast tissue, suppresses proliferation and detachment of MCF-7
breast cancer cells. The objective of the current study was to determine the
presence and characteristics of binding sites for these endogenous putative
cancer-regulating steroid hormones. Radiolabeled 5alphaP and 3alphaHP were used
in radioligand binding assays on MCF-7 cell (membrane, cytosolic, and nuclear)
fractions. Binding of [(3)H]5alphaP and [(3)H]3alphaHP was observed only in the
plasma membrane fraction, whereas estradiol binding sites were confirmed in the
cytosolic and nuclear fractions. The respective membrane binding sites exhibited
specificity for the 5alphaP and 3alphaHP ligands with no appreciable displacement
at 200- to 500-fold excess by other steroids. The association rate constants were
calculated as 0. 107/min and 0.0089/min and the dissociation rate constants were
0. 049 9 and 0.011 for 5alphaP and 3alphaHP, respectively. Saturation analyses
indicated single classes of molecules with dissociation constants of 4.5 and 4.87
nM and receptor densities of 486 and 629 fmol/mg protein, respectively, for
5alphaP and 3alphaHP. Exposure of MCF-7 cells to estradiol for 1, 24, 48, and 72
h resulted in 2.3, 4. 2-, 2.99-, and 1.7-fold increases, respectively, in 5alphaP
receptor density. 3alphaHP resulted in partial suppression of the
estradiol-mediated increase in 5alphaP receptor density. This is the first report
of receptors for the progesterone metabolites, 5alphaP and 3alphaHP, of their
occurrence in breast cancer cell membranes, and of the induction of 5alphaP
receptors by estradiol. The results provide further support for the potential
importance of progesterone metabolites in breast cancer.
Copyright 2000 Academic Press.

Breast Cancer Res. 2013 May 11;15(3):R38.
Progesterone metabolites regulate induction, growth, and suppression of estrogen-
and progesterone receptor-negative human breast cell tumors.
Wiebe JP(1), Zhang G(2,)(3), Welch I(4), Cadieux-Pitre HA(5).
(1)Department of Biology, The University of Western Ontario, London, Ontario,
N6A5B7, Canada. [email protected] (2)Department of Biology, The University of Western
Ontario, London, Ontario, N6A5B7, Canada. [email protected].
(3)Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected]. (4)Department of Animal Care & Veterinary Services
and Department of Physiology and Pharmacology, Medical Sciences Building, The
University of Western Ontario, London, Ontario, N6A 5C1, Canada. [email protected].
(5)Department of Animal Care & Veterinary Services, Medical Sciences Building,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected].
INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each
year, a large proportion is characterized as hormone receptor negative, lacking
estrogen receptors (ER) and/or progesterone receptors (PR). Patients with
receptor-negative tumors do not respond to current steroid hormone-based
therapies and generally have significantly higher risk of recurrence and
mortality compared with patients with tumors that are ER- and/or PR-positive.
Previous in vitro studies had shown that the progesterone metabolites,
5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively,
exhibit procancer and anticancer effects on receptor-negative human breast cell
lines. Here in vivo studies were conducted to investigate the ability of 5αP and
3αHP to control initiation, growth, and regression of ER/PR-negative human breast
cell tumors.
METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into
mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP
treatments on tumor initiation, growth, suppression/regression, and
histopathology were assessed in five separate experiments. Specific
radioimmunoassays and gas chromatography-mass spectrometry were used to measure
5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were
significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were
applied simultaneously, the stimulatory effects of 5αP were abrogated by the
inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to
5αP-induced tumor initiation resulted in suppression of further tumorigenesis and
regression of existing tumors. The levels of 5αP in tumors, regardless of
treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP
ratios were about fivefold higher than in serum, indicating significant changes
in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast
tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and
3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by
5αP and suppressed by 3αHP, the outcome depending on the relative concentrations
of these two hormones in the microenvironment in the breast regions. The findings
show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative
tumors and that treatment with 3αHP can effectively block tumorigenesis and cause
existing tumors to regress. The results provide the first hormonal theory to
explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis
that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster
normalcy in noncancerous breast regions. The findings suggest new diagnostics
based on the relative levels of these hormones and new approaches to prevention
and treatment of breast cancers based on regulating the levels and action
mechanisms of anti- and pro-cancer progesterone metabolites."

Not sure if you saw my edit or sent these to Peat before I edited my post. I think getting some clarity on that question about progesterone being potentially dangerous for breast cancer unless taken with a 5-AR inhibitor is really important.
Thanks a million.

 

[DaveFoster]

Q: "He's got a new 5a-dihydroprogesterone, just hit the streets today."

Lol, and then Ray said, "Yeah man, just snort some of that shiz; it's good for teh estrogen brah."

 

[Pointless]

Not sure if you saw my edit or sent these to Peat before I edited my post. I think getting some clarity on that question about progesterone being potentially dangerous for breast cancer unless taken with a 5-AR inhibitor is really important.
Thanks a million.

It seems like the story is, from what I gathered from the references he cited, is that 5a-DHP activates MAPK, while progesterone inhibits it. This leads to tumors even in progesterone and estrogen receptor negative cell lines. The researchers tested multiple cell lines, also.

 

[jaguar43]

Nothing, that is why the pharma industry is all over allopregnanolone - i.e. immediate metabolite of 5a-DHP, which btw can convert back into 5a-DHP when given in higher doses. So, in effect, the safety of 5a-DHP has been indirectly studied in humans due to the clinical trials with high doses allopregnanolne, which elevates 5a-DHP levels.

Here is Ray Peat on the reason why the pharamcietucal industry is gravitating towards allopregnanolone.

"The industry is also interested in metabolites of progesterone, such as allopregnanlone, which is therapeutic for dementia, but which ( being near the end of a metabolic sequence) might not have the radically restorative functions of progesterone, making it a better product for their business." - Ray PEat's Newsletter Protecting and restoring nerves 2014 page 4

 

[milk_lover]

I emailed Peat the following question:

"There is a new product released by a guy who follows your work. It’s 5α-DHP dissolved in MCT and mixed tocopherols. I copied and pasted the main page of the product below. Could you tell me your thoughts about it before I order one? It sounds promising. Lots of thanks. " And then I copied and pasted haidut's product main page in the email.

He replied with the following:


"The farther a substance is from its precursor material, the easier it is to cause unwanted effects when supplementing it.

J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):166-76.
Mechanism of action of the breast cancer-promoter hormone, 5α-dihydroprogesterone
(5αP), involves plasma membrane-associated receptors and MAPK activation.
Wiebe JP(1), Pawlak KJ(2), Kwok A(3).
(1)Department of Biology, The University of Western Ontario, London, ON N6A 5B7,
Canada. Electronic address: [email protected]. (2)Department of Physiology, School of
Medicine, Zirve University, Gaziantep, Turkey. (3)Department of Biology, The
University of Western Ontario, London, ON N6A 5B7, Canada.
Previous studies have shown that breast tissues and breast cell lines can convert
progesterone to 5α-pregnane-3,20-dione (5aP), and that 5αP stimulates breast cell
proliferation and detachment in vitro, and tumor formation in vivo, regardless of
presence or absence of receptors for progesterone (PR) or estrogen (ER). Recently
it was demonstrated, both in vitro and in vivo, that pro-cancer actions
attributed to administered progesterone are due to the in situ produced 5αP.
Because of the significant role of 5αP in breast cancers, it is important to
understand its molecular mechanisms of action. The aims of the current studies
were to identify 5αP binding sites and to determine if the mechanisms of action
of 5αP involve the mitogen-activated protein kinase (MAPK), extracellular
signal-regulated protein kinases (ERK1/2) pathway. Binding studies, using
tritium-labeled 5αP ([(3)H]5αP), carried out on membrane, cytosol and nuclear
fractions from human breast cells (MCF-7, PR/ER-positive; MDA-MB-231,
PR/ER-negative) and on highly enriched membrane fractions, identified the plasma
membrane as the site of ligand specific 5αP receptors. Localization of 5αP
receptors to the cell membrane was confirmed visually with fluorescently labeled
conjugate (5αP-BSA-FITC). Treatment of cells with either 5αP or
membrane-impermeable 5αP-BSA resulted in significant increases in cell
proliferation and detachment. 5αP and 5αP-BSA equally activated the MAPK/ERK1/2
pathway as evidenced by phosphorylation of ERK1/2. Inhibitors (PD98059,
mevastatin and genistein) of specific sites along the Ras/Raf/MEK/ERK signaling
pathway, blocked the phosphorylation and concomitantly inhibited 5αP-induced
stimulation of cell proliferation and detachment. The study has identified high
affinity, stereo-specific binding sites for 5αP that have the characteristics of
a functional membrane 5αP receptor, and has shown that the cancer-promoter
actions of 5αP are mediated from the liganded receptor via the MAPK/ERK1/2
signaling cascade. The findings enhance our understanding of the role of the
progesterone metabolite 5αP in breast cancer and should promote new approaches to
the development of breast cancer diagnostics and therapeutics.

Endocrinology. 2003 Dec;144(12):5650-7. Epub 2003 Sep 11.
Distinct molecular pathways mediate progesterone-induced growth inhibition and
focal adhesion.
Lin VC(1), Woon CT, Aw SE, Guo C.
(1)Department of Clinical Research, Singapore General Hospital, School of
Biological Sciences, School, Singapore 637616. [email protected].
We have reported previously that reactivation of progesterone receptor (PR)
expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer
cells enabled progesterone to inhibit cell growth and invasiveness, and to induce
remarkable focal adhesions. The present study addressed molecular mechanisms that
mediate these anticancer effects of progesterone in the PR-transfected breast
cancer cells ABC28. In response to progesterone treatment are the marked
up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and
decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for
G1 progression and during cell mitosis. Progesterone also induced down-regulation
of phosphorylated MAPK (p42/44 MAPK).Furthermore, this study also demonstrated
that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also
caused reduction of cyclin D1 level and inhibition of cell proliferation. These
results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms
mediating progesterone's growth-inhibitory effect. On the other hand,
progesterone-induced focal adhesion is mediated by separate pathway. Whereas
PD98059 exhibited no effects on cell adhesion, inhibitory antibody to
beta1-integrin was able to reverse progesterone-induced focal adhesion and
progesterone-induced increase in the phosphorylation of focal adhesion kinase. On
the other hand, beta1-integrin antibody had no effect on progesterone-mediated
growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1
and phosphorylation of P42/P44 MAPK. In the context of complex functions of
progesterone in breast cancer and reproductive organs, identification of distinct
pathways offers new strategies for designing therapeutic agents to target the
specific pathway so as to minimize the side effects.

J Steroid Biochem Mol Biol. 2005 Nov;97(3):278-88.
Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A
breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated
by the progesterone metabolites, 3alpha-dihydroprogesterone and
20alpha-dihydroprogesterone, with associated changes in cell proliferation and
detachment.
Pawlak KJ(1), Zhang G, Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, Department of Biology, University
of Western Ontario, London, Canada.
Previous studies have shown that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity
in breast cell lines and that specific, high affinity receptors for 5alphaP are
located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7
cells. The aim of this study was to determine the effects of the mitogenic
(estradiol; 5alphaP) and anti-mitogenic (3alpha-hydroxy-4-pregnen-20-one,
3alphaHP; 20alpha-hydroxy-4-pregnen-3-one, 20alphaHP) endogenous steroid hormones
on 5alphaP receptor (5alphaP-R) numbers and on cell proliferation and adhesion of
MCF-7 and MCF-10A cells. Exposure of MCF-7 cells for 24h to estradiol or 5alphaP
resulted in significant (p < 0.05-0.001) dose-dependent increases in 5alphaP-R
levels. Conversely, treatment with 3alphaHP or 20alphaHP resulted in significant
(p < 0.05-0.01) dose-dependent decreases in 5alphaP-R levels. Treatment with one
mitogenic and one anti-mitogenic hormone resulted in inhibition of the
mitogen-induced increases, whereas treatment with two mitogenic or two
anti-mitogenic hormones resulted in additive effects on 5alphaP-R numbers.
Treatments with cycloheximide and actinomycin D indicate that changes in
5alphaP-R levels depend upon transcription and translation. The non-tumorigenic
breast cell line, MCF-10A, was also shown to posses specific, high affinity
plasma membrane receptors for 5alphaP that were up-regulated by estradiol and
5alphaP and down-regulated by 3alphaHP. Estradiol binding was demonstrated in
MCF-10A cell membrane fractions and may explain the estradiol action in these
cells that lack intracellular ER. In both MCF-7 and MCF-10A cells, the increases
in 5alphaP-R due to estradiol or 5alphaP, and decreases due to 3alphaHP or
20alphaHP correlate with respective increases and decreases in cell proliferation
as well as detachment. These results show distribution of 5alphaP-R in several
cell types and they provide further evidence of the significance of progesterone
metabolites and their novel membrane-associated receptors in breast cancer
stimulation and control. The findings that 3alphaHP and 20alphaHP down-regulate
5alphaP-R and suppress mitogenic and metastatic activity suggest that these
endogenous anti-mitogenic progesterone metabolites deserve considerations in
designing new breast cancer therapeutic agents.

Biochem Biophys Res Commun. 2000 Jun 16;272(3):731-7.
Plasma membrane receptors for the cancer-regulating progesterone metabolites,
5alpha-pregnane-3,20-dione and 3alpha-hydroxy-4-pregnen-20-one in MCF-7 breast
cancer cells.
Weiler PJ(1), Wiebe JP.
(1)Hormonal Regulatory Mechanisms Laboratory, University of Western Ontario,
London, Canada.
Recent observations indicate that the progesterone metabolite,
5alpha-pregnane-3,20-dione (5alphaP), which is produced at higher levels in
tumorous breast tissue, promotes cell proliferation and detachment, whereas
3alpha-hydroxy-4-pregnen-20-one (3alphaHP), which is produced at higher levels in
nontumorous breast tissue, suppresses proliferation and detachment of MCF-7
breast cancer cells. The objective of the current study was to determine the
presence and characteristics of binding sites for these endogenous putative
cancer-regulating steroid hormones. Radiolabeled 5alphaP and 3alphaHP were used
in radioligand binding assays on MCF-7 cell (membrane, cytosolic, and nuclear)
fractions. Binding of [(3)H]5alphaP and [(3)H]3alphaHP was observed only in the
plasma membrane fraction, whereas estradiol binding sites were confirmed in the
cytosolic and nuclear fractions. The respective membrane binding sites exhibited
specificity for the 5alphaP and 3alphaHP ligands with no appreciable displacement
at 200- to 500-fold excess by other steroids. The association rate constants were
calculated as 0. 107/min and 0.0089/min and the dissociation rate constants were
0. 049 9 and 0.011 for 5alphaP and 3alphaHP, respectively. Saturation analyses
indicated single classes of molecules with dissociation constants of 4.5 and 4.87
nM and receptor densities of 486 and 629 fmol/mg protein, respectively, for
5alphaP and 3alphaHP. Exposure of MCF-7 cells to estradiol for 1, 24, 48, and 72
h resulted in 2.3, 4. 2-, 2.99-, and 1.7-fold increases, respectively, in 5alphaP
receptor density. 3alphaHP resulted in partial suppression of the
estradiol-mediated increase in 5alphaP receptor density. This is the first report
of receptors for the progesterone metabolites, 5alphaP and 3alphaHP, of their
occurrence in breast cancer cell membranes, and of the induction of 5alphaP
receptors by estradiol. The results provide further support for the potential
importance of progesterone metabolites in breast cancer.
Copyright 2000 Academic Press.

Breast Cancer Res. 2013 May 11;15(3):R38.
Progesterone metabolites regulate induction, growth, and suppression of estrogen-
and progesterone receptor-negative human breast cell tumors.
Wiebe JP(1), Zhang G(2,)(3), Welch I(4), Cadieux-Pitre HA(5).
(1)Department of Biology, The University of Western Ontario, London, Ontario,
N6A5B7, Canada. [email protected] (2)Department of Biology, The University of Western
Ontario, London, Ontario, N6A5B7, Canada. [email protected].
(3)Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected]. (4)Department of Animal Care & Veterinary Services
and Department of Physiology and Pharmacology, Medical Sciences Building, The
University of Western Ontario, London, Ontario, N6A 5C1, Canada. [email protected].
(5)Department of Animal Care & Veterinary Services, Medical Sciences Building,
The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
[email protected].
INTRODUCTION: Of the nearly 1.4 million new cases of breast cancer diagnosed each
year, a large proportion is characterized as hormone receptor negative, lacking
estrogen receptors (ER) and/or progesterone receptors (PR). Patients with
receptor-negative tumors do not respond to current steroid hormone-based
therapies and generally have significantly higher risk of recurrence and
mortality compared with patients with tumors that are ER- and/or PR-positive.
Previous in vitro studies had shown that the progesterone metabolites,
5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively,
exhibit procancer and anticancer effects on receptor-negative human breast cell
lines. Here in vivo studies were conducted to investigate the ability of 5αP and
3αHP to control initiation, growth, and regression of ER/PR-negative human breast
cell tumors.
METHODS: ER/PR-negative human breast cells (MDA-MB-231) were implanted into
mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP
treatments on tumor initiation, growth, suppression/regression, and
histopathology were assessed in five separate experiments. Specific
radioimmunoassays and gas chromatography-mass spectrometry were used to measure
5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS: Onset and growth of ER/PR-negative human breast cell tumors were
significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were
applied simultaneously, the stimulatory effects of 5αP were abrogated by the
inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to
5αP-induced tumor initiation resulted in suppression of further tumorigenesis and
regression of existing tumors. The levels of 5αP in tumors, regardless of
treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP
ratios were about fivefold higher than in serum, indicating significant changes
in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS: The studies showed that estrogen/progesterone-insensitive breast
tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and
3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by
5αP and suppressed by 3αHP, the outcome depending on the relative concentrations
of these two hormones in the microenvironment in the breast regions. The findings
show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative
tumors and that treatment with 3αHP can effectively block tumorigenesis and cause
existing tumors to regress. The results provide the first hormonal theory to
explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis
that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster
normalcy in noncancerous breast regions. The findings suggest new diagnostics
based on the relative levels of these hormones and new approaches to prevention
and treatment of breast cancers based on regulating the levels and action
mechanisms of anti- and pro-cancer progesterone metabolites."



So it looks like Peat does't like to supplement the daughter steroids and prefers the parent steroids like pregnenolone, progesterone, DHEA etc.

 

[Wagner83]

Poor Peat , at least have only one guy of the forums ask the questions and send the studies!

From what I remember he was quite curious and interested in supplementing with a minor amount of dht.