"The Farther A Substance Is From Its Precursor Material, The Easier It Is To Cause Unwanted Effects

[Ron J]

when supplementing it."
It's supposed to be a Ray Peat quote, but I'm not sure. I was under the impression that downstream hormones are safer.

 

[Mountain]

I think he might mean that there will necessarily be more processing steps and chances for contamination.

 

[DaveFoster]

@Mountain I completely disagree, but that's true besides.

Peat believes in biological intelligence; the body converts cholesterol into pregnenolone, and then pregnenolone into other steroids as needed.

Downstream hormones are often more dangerous, not safer. The order of safety would be pregnenolone > progesterone > DHEA, with DHT and related molecules being next. The chance of HPTA axis suppression with testosterone and its derivatives is also a factor.

 

[Ron J]

@Mountain I completely disagree, but that's true besides.

Peat believes in biological intelligence; the body converts cholesterol into pregnenolone, and then pregnenolone into other steroids as needed.

Downstream hormones are often more dangerous, not safer. The order of safety would be pregnenolone > progesterone > DHEA, with DHT and related molecules being next. The chance of HPTA axis suppression with testosterone and its derivatives is also a factor.

A lot of people report estrogen symptoms from DHEA. I haven't seen many(if any) success threads/comments from DHEA.

 

[DaveFoster]

A lot of people report estrogen symptoms from DHEA. I haven't seen many(if any) success threads/comments from DHEA.

I continue to have positive experiences with DHEA and pregnenolone. DHT would be safer if not for the higher likelihood of suppression, (but DHEA can cause this as well in higher dosages).

 

[Ron J]

I continue to have positive experiences with DHEA and pregnenolone. DHT would be safer if not for the higher likelihood of suppression, (but DHEA can cause this as well in higher dosages).

Was looking at your threads and didn't find anything(yet) in regards to DHEA. Mind sharing the benefits?

 

[DaveFoster]

Was looking at your threads and didn't find anything(yet) in regards to DHEA. Mind sharing the benefits?

Pansterone ( a mixture of pregnenolone and DHEA) has some noticeable mood benefits; it's one of the view things that directly improves my mood. The other would be coffee (and mirtazapine of course).

The pregnenolone has a calming effect, while the DHEA seems to be more stimulating. I've used both separately in the past, and DHEA definitely has an androgenic effect: improved confidence, outlook, drive, and purpose. You need to be sure your thyroid is good, first.

 

[Ron J]

Pansterone ( a mixture of pregnenolone and DHEA) has some noticeable mood benefits; it's one of the view things that directly improves my mood. The other would be coffee (and mirtazapine of course).

The pregnenolone has a calming effect, while the DHEA seems to be more stimulating. I've used both separately in the past, and DHEA definitely has an androgenic effect: improved confidence, outlook, drive, and purpose. You need to be sure your thyroid is good, first.

Thank you.

 

[milk_lover]

Yes that was his response after I emailed him about 5α-DHP. I think you can find it in the email thread and he gave studies in that response. Or maybe I posted it in another thread about the safety of 5α-DHP..

 

[milk_lover]

My 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. "

Ray Peat: "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."

 

[haidut]

Yes that was his response after I emailed him about 5α-DHP. I think you can find it in the email thread and he gave studies in that response. Or maybe I posted it in another thread about the safety of 5α-DHP..

The 5a-DHP is not far off from pregnenolone - only 2 steps away, same as with DHEA. But I agree with Peat's general statement that downstream hormones are more likely to cause side effects. Probably because they are more "specific" - i.e. the organism synthesizes them for more specific reasons/needs, so if the need is not there and the steroid is elevated there is more chance of side effects. This credo is basically the opposite of what pharma drugs do - all of them chase specificity as the hallmark of a "clean" drug and as a result cause numerable side effects (which is considered perfectly acceptable, even if the side effect is deadly). In contrast, a drug that is systemic (non-specific) is considered "dirty" and undesirable.
Dirty drug - Wikipedia

Yes, that's how opposite to the truth medicine and pharma companies have gotten