New IdeaLabs Product – 3α-Dihydroprogesterone (3α-DHP)
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As many of my readers know, the medical industry has been quietly increasing its interest in and clinical trials with so-called “neurosteroids”, most of them members of the pregnane family. I think the term “neurosteroid” as used by mainstream medicine is a misnomer as it is used selectively for only a few of all the known steroids, despite the fact that virtually all of them have been demonstrated to have a central (brain) effect. For example, currently the label “neurosteroid” is applied almost exclusively to steroids such as pregnenolone, progesterone, allopregnanolone and various of their synthetic derivatives, though steroid families such as estrogens, androgens, mineralo/gluco-corticoids, and even thyroid hormones have all been demonstrated to have potent and rapid central effects as well, with indisputable influence on mood, cognition, various neurological conditions, traumas (e.g. TBI) and even cancer.
Recently, the FDA approved the progesterone derivative allopregnanolone (3α, 5α-tetrahydroprogesterone), commonly known as Allo or AlloP, as a treatment for post-partum depression. In addition, multiple companies are running clinical trials with that steroid for wide range of other conditions including dementia (e.g. Alzheimer Disease), anxiety disorders, autism, psychotic states (e.g. schizophrenia), post-traumatic stress disorder (PTSD), and even direct brain damage states such as traumatic brain injury (TBI) as well as its chronic form known as chronic traumatic encephalopathy (CTE). As of now, the only condition for which AlloP has been approved is postpartum depression with expectations that the steroid will soon be also approved for depression of any origin. The currently approved formulation is through IV infusion, but some of the new formulations currently being tested are meant for oral use, and use a preparation very close to the ideas of Dr. Peat for using long-chain fats and vitamin E to circumvent first-pass metabolism of any steroid and ensure most of the steroid gets absorbed through the lymphatic system. As such, selling AlloP has become very legally risky.
Interestingly enough, the first commercial antidepressant of the SSRI class known as fluoxetine (Prozac) was found to increase the activity and expression of an enzyme called 3α-hydroxysteroid dehydrogenase (3α-HSD), which is one of the major steps in synthesizing allopregnanolone from progesterone.
https://www.ucsf.edu/news/1999/11/97489/scientists-identify-new-pathway-antidepressant-action
https://www.pnas.org/doi/10.1073/pnas.96.23.13512
Since levels of allopregnanolone have been consistently found to increase after fluoxetine administration, and allopregnanolone levels were found to be universally low in people with depression (as well as many other brain/mood conditions) the hypothesis was that it was allopregnanolone that was the true antidepressant, with fluoxetine functioning only as a trigger for the synthesis of that “neurosteroid”.
https://pubmed.ncbi.nlm.nih.gov/37746458/
However, this hypothesis is incomplete since fluoxetine was found to increase activity and expression of mostly 3α-HSD, and while this MAY results in higher allopregnanolone levels it does not guarantee it, since the cascade has to also pass through the enzyme 5α-reductase (5-AR) in order to synthesize allopregnanolone. In fact, the steps of allopregnanolone synthesis are as follows: progesterone -> 5α-dihydroprogesterone (5-AR activity) -> allopregnanolone (3α-reductase activity). If fluoxetine selectively increases the activity of only 3α-HSD, then the only thing that can be said for sure is that fluoxetine would increase the levels of a steroid that takes progesterone as input and produces a 3α-reduced steroid, which is a steroid with a hydroxyl group (OH) on position C-3, in the alpha configuration. Once progesterone goes through 3α-HSD, and produces a C-3-ol steroid, the reaction terminates there, since that output steroid cannot undergo processing by 5-AR, as the latter can only accept as input steroids with a keto group on C-3 (progesterone, testosterone, cortisol, etc). However, since the enzyme 3α-HSD is bi-directional (oxido-reductase), the end steroid output may get converted back to progesterone. The output of the progesterone being processed by 3α-HSD is the steroid 3α-Dihydroprogesterone (3α-DHP), and if fluoxetine works primarily by increasing 3α-HSD activity and levels, then a more appropriate hypothesis would be that the anti-depressant and anti-anxiety effects of fluoxetine may be due more to the increased levels of 3α-DHP, and not so much on the increased levels of allopregnanolone.
https://en.wikipedia.org/wiki/3%CE%B1-Dihydroprogesterone
Interestingly enough, 3α-DHP has been found to have the same affinity and strength as a GABA agonist as allopregnanolone, and the latter is known as the most potent endogenous GABA agonist agent. As such, multiple studies have demonstrated that 3α-DHP has similar anxiolytic, sedative and analgesic effects as allopregnanolone. In addition, levels of 3α-DHP have been found to be low in many conditions where allopregnanolone levels have also been found to be low.
“…3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid.[1] It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone.[1] 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action.[1] In accordance, it has anxiolytic effects in animals.[2] 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties.[1] Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride.[1] No data were available on the progestogenic activity of 3α-DHP as of 1977.[3] Levels of 5α-DHP have been quantified.[4]”
Strong GABA agonists are known to have a cortisol-lowering effects and there are several published case reports showing successful treatment of Cushing disease/syndrome in some people using the anti-anxiety benzodiazepine drugs (also GABA agonists, but more selective). Being the strongest endogenous GABA agonist, allopregnanolone has also been demonstrated to have cortisol-lowering effects in humans.
https://pubmed.ncbi.nlm.nih.gov/20158297
https://pubmed.ncbi.nlm.nih.gov/8946427/
https://pubmed.ncbi.nlm.nih.gov/36139100
Cortisol is a proven causal factor in depression, confirmed by multiple studies demonstrating rapid antidepressant effects of glucocorticoid antagonists (e.g. Mifepristone/RU486) in both animals and humans, as well as by rapid depressive effects caused by synthetic (e.g. dexamethasone) and natural (e.g. cortisol) glucocorticoid agonists. Since allopregnanolone has been shown to lower cortisol in humans that may explain most of its anti-depressant effects, as well as its anxiolytic effects.
https://www.newscientist.com/article/dn9516-abortion-drug-could-rapidly-treat-depression/
https://doi.org/10.1016/j.steroids.2022.109058
https://link.springer.com/article/10.1134/S2079059717010142
https://pubmed.ncbi.nlm.nih.gov/34071053
As the Wiki article above states, 3α-DHP is as effective as allopregnanolone in terms of GABA activity, and likely has the same mental/physiological effects. Also, unlike allopregnanolone, 3α-DHP is not affected by administration of 5-AR inhibitor drugs such as finasteride, and is not currently regulated by medical authorities (e.g. FDA) in the US or other any other of the 30+ countries I was able to check.
https://pubmed.ncbi.nlm.nih.gov/7914815/
“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to an aversive, anxiety-inducing, predator (cat) odor were examined in an odor preference test. Control untreated mice displayed an anxiogenic response to the cat odor, spending a minimal amount of time in a Y-maze in the vicinity of the cat odor. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP had an anxiolytic action, resulting in significant dose-related (0.01-1.0 micrograms) increases in the amount of time spent in the proximity of the cat odor. These anxiolytic effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP) having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the response to cat odor indicating that the anxiolytic actions of 3 alpha HP were unlikely to be related to any analgesic effects. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results indicate that the allylic neurosteroid 3 alpha HP has anxiolytic actions involving interactions with the GABAA receptor.”
https://pubmed.ncbi.nlm.nih.gov/9870343/
“…Here we show that brief exposure of male mice to an ELF magnetic field (30 min, 60 Hz, 141 microT peak) significantly reduces the analgesic effects arising from intracerebroventricular (i.c.v.) administration of the centrally produced allylic neuroactive steroid, 3alpha-hydroxy-4-pregnen-20-one (3alphaHP) and that the dihydropyridine (DHP) calcium channel antagonists, diltiazem and nifedipine, block the inhibitory effects of the 60 Hz ELF on 3alphaHP-induced analgesia. These results indicate that exposure to 60 Hz ELF affects the analgesic effects of neuroactive steroids such as 3alphaHP through alterations in calcium channel function. These findings raise the possibility that ELF magnetic fields may, in part, exert their actions through effects on diverse neuroactive steroid modulated processes.”
https://pubmed.ncbi.nlm.nih.gov/3147122/
“…This allylic steroid elicited significant, dose-dependent (0.001-1.0 micrograms) analgesic responses for 90-150 min after injection. These analgesic effects of 3A4P were stereospecific, the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3B4P) failing to affect the nociceptive responses. The analgesic effects of 3A4P were blocked by peripheral administrations of the GABA antagonists, bicuculline and picrotoxin, and reduced by the benzodiazepine antagonist, Ro 15-1788. The exogenous opiate antagonist, naloxone, and the putative endogenous opioid antagonist, Tyr-MIF-1 (Pro-Leu-Gly-amide), also reduced 3A4P-induced analgesia, while i.c.v. administration of 3A4P (0.001 and 0.01 micrograms) itself attenuated the analgesic effects arising from peripheral administrations of opiate receptor agonist, morphine. In addition, the calcium channel antagonists, nifedipine and verapamil, enhanced 3A4P-induced analgesia but had no evident effects on the actions of 3B4P. These results suggest that the central analgesic effects of the FSH-suppressing steroid, 3A4P, arise via benzodiazepine–GABA–opiate mechanisms and calcium channels.”
The interesting properties of 3α-DHP are not exhausted by its close mimicry/overlap with allopregnanolone. The studies below suggest that it has a number of other interesting effects, at least in animals, include unique anti-cancer effects NOT shared by allopregnanolone. Since one of the tumor cell lines used in many of those cancer studies was the estrogen-sensitive (ER+) line known as MCF-7, a reasonable conclusion may be that 3α-DHP has anti-estrogenic effects, not shared by its cousin allopregnanolone, as other estrogen antagonists have also showed anti-cancer effects in MCF-7 models. For the record, 3α-DHP also demonstrated inhibitory effects on tumor growth from estrogen- and progesterone-negative cell likes, which suggests its effects are generic/systemic and not only focused on a specific steroid pathway.
https://pubmed.ncbi.nlm.nih.gov/25927181/
“…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.”
https://pubmed.ncbi.nlm.nih.gov/19931389/
“…The studies were conducted on tumorigenic (MCF-7, MDA-MB-231, T47D) and non-tumorigenic (MCF-10A) human breast cell lines, employing several methods to assess the effects of the hormones on cell proliferation, mitosis, apoptosis and expression of Bcl-2, Bax and p21. In all four cell lines, 5alphaP increased, whereas 3alphaHP decreased cell numbers, [(3)H]thymidine uptake and mitotic index. Apoptosis was stimulated by 3alphaHP and suppressed by 5alphaP. 5alphaP resulted in increases in Bcl-2/Bax ratio, indicating decreased apoptosis; 3alphaHP resulted in decreases in Bcl-2/Bax ratio, indicating increased apoptosis. The effects of either 3alphaHP or 5alphaP on cell numbers, [(3)H]thymidine uptake, mitosis, apoptosis, and Bcl-2/Bax ratio, were abrogated when cells were treated simultaneously with both hormones. The expression of p21 was increased by 3alphaHP, and was unaffected by 5alphaP. The results provide the first evidence that 5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis. The opposing effects of 5alphaP and 3alphaHP were observed in all four breast cell lines examined and the data suggest that all breast cancers (estrogen-responsive and unresponsive) might be suppressed by blocking 5alphaP formation and/or increasing 3alphaHP. ”
https://pubmed.ncbi.nlm.nih.gov/15212687
“…Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5α-reductase (5αR) and lower 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO activities. The resulting higher levels of 5α-reduced progesterone metabolites such as 5α-pregnane-3,20-dione (5αP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression.”
“…The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of SRD5A1 (5αR1) and SRD5A2 (5αR2) is elevated, and expression of AKR1C1 (20α-HSO), AKR1C2 (3α-HSO3) and AKR1C3 (3α-HSO2) is reduced in tumorous as compared to normal breast tissue. The changes in progesterone metabolizing enzyme expression levels help to explain the increases in mitogen/metastasis inducing 5αP and decreases in mitogen/metastasis inhibiting 3αHP progesterone metabolites found in breast tumor tissues. Understanding what causes these changes in expression could help in designing protocols to prevent or reverse the changes in progesterone metabolism associated with breast cancer.”
Furthermore, another study demonstrated striking spermatogenic effects of 3α-DHP, which were much stronger than the spermatogenic effects of testosterone. However, unlike testosterone, DHT and other related steroids, 3α-DHP did not display androgenic effects. Assuming allopregnanolone has similar effects, I would not be surprised if we soon see clinical trials for allopregnanolone (and/or, God forbid, 3α-DHP) as treatments for infertility, especially considering the skyrocketing rates of this issue in most Western/developed countries.
https://pubmed.ncbi.nlm.nih.gov/2502196/
“…The effect of 3 alpha-hydroxy-4-pregnen-3-one (3HP), a Sertoli cell steroid, on spermatogenesis was examined in normal and gonadotropin-suppressed rats, through s.c. as well as direct intratesticular injections. Early experiments employing normal prepubertal male rats indicated that 3HP, when administered at 65 micrograms/100 g BW daily for 15 days, was capable of stimulating pachytene spermatocyte number to 149% of untreated control numbers. It was of interest to determine if this effect could be amplified in gonadotropin-suppressed animals. Neonatally estrogenized rats (500 micrograms estradiol benzoate in 0.1 ml oil at 2 days) were treated on alternate days with 3HP (100 micrograms/100 g BW) for 3 wk, starting at 7 days of age. This treatment significantly increased the number of spermatocytes per tubule cross section from 17.3 +/- 1.9 (in estradiol benzoate-only animals) to 47.1 +/- 7.9 (p less than 0.01). In a similar study, 100 micrograms/100 g BW of testosterone propionate could stimulate spermatocyte number to only 15.1 +/- 2.2 cells per tubule cross section versus estradiol benzoate-only numbers. A single intratesticular injection of 3HP (2 ng in 2.0 microliters oil) in Methallibure-treated rats resulted in a significant increase in late pachytene spermatocyte numbers from 0.77 +/- 0.12 in Methallibure-only-treated rats to 1.70 +/- 0.10 (p less than 0.001) cells per tubule cross section in 28-day-old rats. However, in this study, no other progesterone metabolite or androgenic steroid (testosterone, 5 alpha-dihydrotestosterone, or 5 alpha-androstan-3 alpha, 17 beta-diol) tested was capable of this level of germ cell stimulation. In conclusion, 3HP appears to have a direct effect on germ cell development within the testis at levels much lower than those shown to be effective for androgens. It does not appear that this effect is mediated through the conversion of 3HP to any C21 or C19 steroids, and appears to be the first report of a Sertoli cell steroid with a possible role in the process of mammalian spermatogenesis.”
https://pubmed.ncbi.nlm.nih.gov/3106016/
“…Treatment of young (15-day-old) intact males with either 3-HP or 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) for 14 days showed that DHT resulted in significant increases in prostate and seminal vesicle weights, while 3-HP showed no apparent androgenic activity. ”
Finally, 3α-DHP seems to have pro-sexual effects (at least in males) as it increased the preference of treated males for the odor of estrous females. While the study discusses GABA agonism by 3α-DHP as the main mechanism in achieving this pro-sexual effects, I suspect there is more at play since the administered GABA abtagonists did not completely block the effect. In my opinion, given the similar structure between 3α-DHP and allopregnanolone, the pro-dopamine and anti-serotonin (5-HT3 blocker) effects of the latter are likely to both be present in the former, and both of those pathways have a known pro-libido and performance enhancing effects.
https://pubmed.ncbi.nlm.nih.gov/8055331/
“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to the odors of estrous female mice were examined in an odor preference test. Control untreated mice displayed a significant preference for the odors of an estrous female, spending more time in a Y-maze in the vicinity of the odors of an estrous than a non-estrous female. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP enhanced male preference for the odors of estrous females, causing a significant dose-related (0.01-1.0 microgram) increase in the amount of time spent in the proximity of the odors of the estrous female, while having no significant effect on the responses to the non-estrous female odors. These effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the responses to female odors suggesting that the enhanced preference for estrous female odors were unlikely to be directly due to any analgesic effects of 3 alpha HP. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results suggest that the neurosteroid 3 alpha HP has facilitatory effects on olfactory mediated male sexual interest or motivation that involve interactions with the GABAA receptor.”
All in all, quite an interesting substance, and given its non-regulated nature we decided to release it as a product to the general public.
The units listed on the label are just for measurement purposes. They do not indicate or suggest optimal dose. Please note that similar to the liquid products sold by companies like Sigma Aldrich, Spectrum Chemical, Alfa Aesar, etc, this product if for lab/research use only.
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3α-DHP is a liquid (very viscous) product containing a bioidentical endogenous neurosteroid known as 3α-dihydroprogesterone (3α-DHP). While that steroid has not been as extensively studied as the closely-related neurosteroid allopregnanolone, 3α-DHP can perhaps be best described as an allopregnanolone mimetic, with similar (though not identical) pharmacological profile and strength (especially on the GABA system). Some of the more unique and interesting properties of 3α-DHP include its anti-cancer effects demonstrated in animal studies, with the notable finding that those anti-cancer effects are NOT shared by neither allopregnanolone nor its precursor neurosteroid 5α-dihydroprogesterone (5α-DHP). In addition, 3α-DHP has demonstrated potent spermatogenic and pro-sexual effects in some animal studies, with the former fax exceeding the effects of any other known and tested steroid (e.g. androgens).Drops per container: about 250
Each drop contains the following ingredients:3α-dihydroprogesterone (CAS 25680-68-6): 1mg
Other ingredients: add product to shopping cart to see info
*******************************************************************************REFERENCES:
https://pubmed.ncbi.nlm.nih.gov/11606426/
https://pubmed.ncbi.nlm.nih.gov/9295205/
https://pubmed.ncbi.nlm.nih.gov/8199276/
https://pubmed.ncbi.nlm.nih.gov/8275952/
https://pubmed.ncbi.nlm.nih.gov/1331405/
https://pubmed.ncbi.nlm.nih.gov/2031864/
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personal effects from it?
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This new product is $69, much more expensive than the Allop product that was removed last week.
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@AinmBeo ok
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@AinmBeo First 5a DHP, than AlloP gone
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@haidut what were the effects compared to 5 A DHP & AlloP?
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haidut, it's always great to see you posting here, as opposed to posting on the Vitamins Are Toxins Forum.
I wish I had stocked up on AlloP before you discontinued it. That stuff would lean out my face and improve my appearance, although I didn't notice any other effects. I can't afford to by this new version on a regular basis, but I may trail it, eventually.
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For 1 mg 3alpha what is the ratio converted to allop ? Also does it need cholesterol to convert compare to Allop that is the final stage ? Does it need T3 and so on ?
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@haidut How it should be applied to women and their cycle? And also morning or evening type of thing? Ah last question any doses suggestions? Thank you so much for all your work and effort!!!
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By the way, the only alternative source for allop (aside from big lab companies like Sigma, which won't sell to citizens), is:
https://russianstarpeptides.com/product/allopregnanolone-5mg-nasal-spray/
Has anyone used this? -
Synchronicity strikes again!
I was thinking about messaging you to ask if you can bring back 5aDHP because I like it so much.
But 3aDHP seems close enough to try.Does it have the some anti-prolactin effect as 5aDHP?
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what did 5a dhp feel like?
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@wester130 like the sweet spot between dopamine and GABA with a little bit of progesterone in it.
I did not get those effects from allopreg.Dare to think.
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@Mauritio when did you use it during the day?
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@AinmBeo
They are scammers, stay away -
it would be interesting to see how this boosts Testosterone
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There's very little studies on this metabolite ...
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" 3α-DHP has also been found to inhibit the secretion offollicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic effects "
"opioid antagonists, like naltrexone, have progonadotropic effects, and can increase luteinizing hormone and testosterone levels."
so are gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone bad for you?
should they be high or low?
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In general, Ray warned against metabolites and downstream hormones.
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@bio3nergetic yeah he wasn't the biggest fan of 5aDHP either. Which is understandable if you see the cancer studies. And Ray was pretty cautious when it comes to supplements in general.
