Effect of Palmitoylethanolamide (PEA) partially inhibited by finasteride - Theory

Palmitoylethanolamide (PEA)

Palmitoylethanolamide is available and is sold under the brand name Normast.


Now here is the kicker … a study which directly links it to finasteride :confused:

Palmitoylethanolamide Stimulation Induces Allopregnanolone Synthesis in C6 Cells and Primary Astrocytes: Involvement of Peroxisome-Proliferator Activated Receptor-α

Palmitoylethanolamide (PEA) regulates many pathophysiological processes in the central nervous system, including pain perception, convulsions and neurotoxicity, and increasing evidence points to its neuroprotective action. In the present study, we report that PEA, acting as a ligand of peroxisome-proliferator activated receptor (PPAR)-α, might regulate neurosteroidogenesis in astrocytes, which, similar to other glial cells and neurones, have the enzymatic machinery for neurosteroid de novo synthesis. Accordingly, we used the C6 glioma cell line and primary murine astrocytes. In the mitochondrial fraction from cells stimulated with PEA, we demonstrated an increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 enzyme (P450scc) expression, both comprising proteins considered to be involved in crucial steps of neurosteroid formation. The effects of PEA were completely blunted by GW6471, a selective PPAR-α antagonist, or by PPAR-α silencing by RNA interference. Accordingly, allopregnanolone (ALLO) levels were increased in supernatant of PEA-treated astrocytes, as revealed by gas chromatography-mass spectrometry, and this effect was inhibited by GW6471. Moreover, PEA showed a protective effect, reducing malondialdehyde formation in cells treated with l-buthionine-(S,R)-sulfoximine, a glutathione depletor and, interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor. A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis. The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-α in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions.

ncbi.nlm.nih.gov/pubmed/21554431

Here is the wiki page for PEA

en.wikipedia.org/wiki/Palmitoylethanolamide

Someone has to get there hands on this medication, Normast would be the best to get.

Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice: involvement of allopregnanolone biosynthesis.

Sasso O, La Rana G, Vitiello S, Russo R, D’Agostino G, Iacono A, Russo E, Citraro R, Cuzzocrea S, Piazza PV, De Sarro G, Meli R, Calignano A.
Source
Department of Experimental Pharmacology, University of Naples Federico II via D. Montesano 49, 80131 Naples, Italy.

Abstract

Palmitoylethanolamde (PEA) is an endogenous lipid neuromodulator that mediates a broad spectrum of pharmacological effects by activation of peroxisome proliferator-activated receptor alpha (PPAR-alpha). Detectable or high levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Here we report evidence that PEA, activating PPAR-alpha receptor and involving neurosteroids de novo synthesis, modulates pentobarbital-evoked hypnotic effect. A single i.c.v. administration of PEA (1-5microg) increases pentobarbital induced loss of righting reflex (LORR) duration in mice. This effect is mimicked by GW7647 (3microg), a synthetic PPAR-alpha agonist, and disappears in PPAR-alpha knockout mice. Antagonism experiments strongly support the engaging of neurosteroidogenic pathway in the increase of LORR duration induced by PEA. This effect disappeared using two inhibitors blocking the key steps of neurosteroids synthesis, aminogluthetimide and finasteride. Moreover, we demonstrated that in brainstem PEA increased the expression of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both involved in neurosteroidogenesis. Accordingly, allopregnanolone (ALLO) levels were in turn higher in brainstem of PEA and pentobarbital treated mice vs pentobarbital alone, as revealed by quantitative analysis using gas chromatography-mass spectrometry. A Our results demonstrate that exogenous administration of PEA, through a PPAR-alpha-dependent mechanism, modulates neurosteroids formation increasing ALLO levels and leading to a positive modulation of GABA(A) receptor. These data further strengthen our previous data on the role of PPAR-alpha in PEA’s actions and could provide a new framework to understand its role in the CNS.

ncbi.nlm.nih.gov/pubmed/19864116


Does this sound like our problem?

Autonomic nervous system

The autonomic nervous system (ANS or visceral nervous system) is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions.[1] The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils, micturition (urination), and sexual arousal. Whereas most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind.

en.wikipedia.org/wiki/Autonomic_nervous_system

To break the Autonomic Nervous system down…

Parasympathetic nervous system

The parasympathetic nervous system (PSNS) is one of the two main divisions of the autonomic nervous system (ANS). The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously. To be specific, the parasympathetic system is responsible for stimulation of “rest-and-digest” activities that occur when the body is at rest, including sexual arousal, salivation, lacrimation (tears), urination, digestion, and defecation. Its action is described as being complementary to that of one of the other main branches of the ANS, the sympathetic nervous system, which is responsible for stimulating activities associated with the fight-or-flight response.

Sympathetic nervous system

Alongside the other two components of the autonomic nervous system, the sympathetic nervous system aids in the control of most of the body’s internal organs. Stress—as in the flight-or-fight response—is thought to counteract the parasympathetic system, which generally works to promote maintenance of the body at rest.

Sensory neurons

The sensory arm is made of “primary visceral sensory neurons” found in the peripheral nervous system (PNS), in “cranial sensory ganglia”: the geniculate, petrosal and nodose ganglia, appended respectively to cranial nerves VII, IX and X. These sensory neurons monitor the levels of carbon dioxide, oxygen and sugar in the blood, arterial pressure and the chemical composition of the stomach and gut content. (They also convey the sense of taste, a conscious perception). Blood oxygen and carbon dioxide are in fact directly sensed by the carotid body, a small collection of chemosensors at the bifurcation of the carotid artery, innervated by the petrosal (IXth) ganglion. Primary sensory neurons project (synapse) onto “second order” or relay visceral sensory neurons located in the medulla oblongata, forming the nucleus of the solitary tract (nTS), that integrates all visceral information. The nTS also receives input from a nearby chemosensory center, the area postrema, that detects toxins in the blood and the cerebrospinal fluid and is essential for chemically induced vomiting or conditional taste aversion (the memory that ensures that an animal which has been poisoned by a food never touches it again). All these visceral sensory informations constantly and unconsciously modulate the activity of the motor neurons of the ANS

Further reading

Sympathetic nervous system

Main article: Sympathetic nervous system
-Promotes a “fight or flight” response, corresponds with arousal and energy generation, and inhibits digestion.
-Diverts blood flow away from the gastro-intestinal (GI) tract and skin via vasoconstriction.
-Blood flow to skeletal muscles and the lungs is enhanced (by as much as 1200% in the case of skeletal muscles).
-Dilates bronchioles of the lung, which allows for greater alveolar oxygen exchange.
-Increases heart rate and the contractility of cardiac cells (myocytes), thereby providing a mechanism for the enhanced blood flow to skeletal muscles.
-Dilates pupils and relaxes the ciliary muscle to the lens, allowing more light to enter the eye and far vision.
-Provides vasodilation for the coronary vessels of the heart.
-Constricts all the intestinal sphincters and the urinary sphincter.
-Inhibits peristalsis.
-Stimulates orgasm.

Parasympathetic nervous system

Main article: Parasympathetic nervous system
-Promotes a “rest and digest” response, promotes calming of the nerves return to regular function, and enhances digestion.
-Dilates blood vessels leading to the GI tract, increasing blood flow. This is important following the consumption of food, due to the greater metabolic demands placed on the body by the gut.
-The parasympathetic nervous system can also constrict the bronchiolar diameter when the need for oxygen has diminished.
-Dedicated cardiac branches of the Vagus and thoracic Spinal Accessory nerves impart Parasympathetic control of the Heart or Myocardium.
-During accommodation, the parasympathetic nervous system causes constriction of the pupil and contraction of the ciliary muscle to the lens, allowing for closer vision.
-The parasympathetic nervous system stimulates salivary gland secretion, and accelerates peristalsis, so, in keeping with the rest and digest functions, appropriate PNS activity mediates digestion of food and indirectly, the absorption of nutrients.
-Is also involved in erection of genitals, via the pelvic splanchnic nerves 2–4.
-Stimulates sexual arousal.


Effects of Spinal Cord Injury on Semen Parameters

Abstract

Neurogenic reproductive dysfunction in men with spinal cord injury (SCI) is common and the result of a combination of impotence, ejaculatory failure, and abnormal semen characteristics. It is well established that the semen quality of men with SCI is poor and that changes are seen as early as 2 weeks after injury. The distinguishing characters of poor quality are abnormal sperm motility and viability. In the majority of the men with SCI, the sperm count is not abnormal. We elaborate on the effects of the SCI on semen parameters that may contribute to poor motility and poor viability.

ncbi.nlm.nih.gov/pmc/articles/PMC2435039/

Section of the study called Testicular Function

Experimental work on acute SCI in rats shows profound effects on the hypothalamic-pituitary-testicular axis by the third day after SCI (19). These changes were temporary, and a normal hormonal milieu was restored by 14 days. The overall conclusion from animal studies rules out hormonal deficiency as the predominant cause of infertility in SCI. Hypothalamic-pituitary-testicular axis dysfunction has been confirmed in humans after SCI, and its severity has been correlated to the level of injury (20). Testosterone, follicle-stimulating hormone, and leuteinizing hormone levels remained altered for 6 weeks in men with paraplegia and for 4 months in men with tetraplegia. Similar dysfunction was also apparent in the HP-adrenal axis with abnormal cortisol secretion in response to adrenocorticotropic hormone in men with SCI (21). Overall, 51% of men with SCI have at least one hormonal abnormality and 86% have some hypothalamic-pituitary axis abnormality (22). Hyperprolactinemia is seen very commonly in SCI and might be contributory to testicular hypofunction (23,24). Although abnormal hormonal levels in urine and blood have been reported in many studies in men with SCI, this does not seem to be the primary cause of infertility because equal numbers of studies report normal findings (25–27).
Historically, nearly 65% of men with SCI have abnormal spermatogenesis on testicular biopsy, and the abnormality is generally independent of duration, level, and severity of the injury (27) Testicular interstitial fibrosis and arrest of spermatogenesis have been reported (27,28). Using quantitative micrometric assessment, researchers found that 65% of men with SCI, compared with noninjured fertile controls, had adequate mean spermatid numbers per tubule that met minimum standards for adequate spermatogenesis (29). However, as a group they had significantly decreased numbers per tubule (30). Hirsch et al noted improvements over the decades in testicular biopsies of men with SCI. He hypothesized that the improvements were related to better bladder management over the decades, including an emphasis on low-pressure voiding (31).

Conclusion to the above study

CONCLUSION

Overall, 51% of men with SCI have at least one hormonal abnormality and 86% have some hypothalamic-pituitary-testicular axis abnormality (21). Despite these abnormal hormonal levels, it does not seem to be the primary cause of infertility in men with SCI, because an equal number of studies report normal results. Males with obstructive azoospermia have similar quantitative parameters of spermatogenesis as that seen in men with SCI, pointing to a postspermatogenic cause for neurogenic infertility. Epididymal function appears sensitive to temperature change and also sensitive to sympathetic nerve integrity; however, there appears to be no correlation between scrotal temperature and quantitative semen parameters of men with SCI.
Maintenance of sperm function requires normal secretions from prostate and seminal vesicles. Dysfunction at this level might result in subfertility. The balance between ROS production and scavenging in men with SCI appears abnormal and may be responsible for infertility. Men with SCI have elevated levels of ROS in their semen. This increase in ROS seems to be at least in part due to an increased oxidative stress and leucocytospermia. There is a correlation between the percentage of patients with normal spermatogenesis and the improvement in bladder management and infection control (31). Semen infection appears to have no effect on sperm count or pregnancy rates. The responsibility for poor sperm motility and viability in SCI seems to have shifted towards the constituents of the seminal plasma.
Autonomic nervous dysfunction seems to affect movement of sperm from the caudal epididymis and proximal vas. Although this may not affect the intrinsic motility of the sperm, it may have an impact on final mature movements. In addition, there is considerable neurogenic impairment to the ejaculation process that requires assisted ejaculation techniques.
The definitive causal mechanism leading to abnormal semen quality in men with SCI remains to be elucidated.

Obviously the injuries in this study are different to ours, i am using it to show the effect the nervous system has on the reproductive system.

You can probably work out what i am getting at, Finasteride has caused damage to the Peripheral nervous system, by the looks more specifically the autonomic nervous system due to the partial inhibition of Palmitoylethanolamide (PEA), among other things a neuroprotective compound.

A few more little nuggets…

pnas.org/content/early/2009/11/18/0907417106


ncbi.nlm.nih.gov/pubmed/19931394


ncbi.nlm.nih.gov/pubmed/21354467


Interestingly the does appear to be a connection between the autonomic nervous system and hair loss…

[The function of the autonomic nervous system in women with androgenetic alopecia].

Abstract

Essential shifts in the autonomic nervous system, detectable by clinical methods and during a dynamic examination (of the autonomic reactivity and autonomic activity provision) were revealed in women suffering from androgenetic alopecia. The status of the autonomic nervous system was analyzed with consideration for the effects of psychogenic factors and the type of hair loss. The findings will help develop approaches to treatment of the condition.

ncbi.nlm.nih.gov/pubmed/2256365


and

Brain-derived nerve factor and neurotrophins in androgenetic alopecia.

Neurotrophic factors, especially BDNF (Brain-derived nerve factor), may be important in mediating the effects of androgens on hair follicles, serving as a negative regulatory control signal. Further studies may lead to novel pharmacological interventions in AGA(androgenetic alopecia).

ncbi.nlm.nih.gov/pubmed/21729031

Nice work Tim, this is very interesting.

Cheers Kazman

Theres more…

N-(2-hydroxyethyl)hexadecanamide(palmitoylethanolamide) is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.

Abstract

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; © exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides (‘ALIAmides’) represent novel therapeutic agents useful in the management of inflammatory disease conditions.

ncbi.nlm.nih.gov/pubmed/8739213

Ties in with viewtopic.php?f=27&t=5661&hilit=inflammatory

N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice.

ncbi.nlm.nih.gov/pubmed/21857095

‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors

Just a note on the TRPV1 receptor, from wiki…



Also there is unbelievably a nystatin link here … first off

biomedcentral.com/content/pdf/1476-511X-9-47.pdf

So there is an interaction between AEA and PEA, it appears that AEA can have bad effects, i wonder if the interaction is one goes up when the other go down?

Anyway…

ncbi.nlm.nih.gov/pmc/articles/PMC2013877/

Very interesting stuff.

I suggest one of us try it

ergomax.nl/Erg-33.html

I ordered some.

I am really interested to see how it goes at this :

Abstract
Palmitoylethanolamde (PEA) is an endogenous lipid neuromodulator that mediates a broad spectrum of pharmacological effects by activation of peroxisome proliferator-activated receptor alpha (PPAR-alpha). Detectable or high levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Here we report evidence that PEA, activating PPAR-alpha receptor and involving neurosteroids de novo synthesis, modulates pentobarbital-evoked hypnotic effect. A single i.c.v. administration of PEA (1-5microg) increases pentobarbital induced loss of righting reflex (LORR) duration in mice. This effect is mimicked by GW7647 (3microg), a synthetic PPAR-alpha agonist, and disappears in PPAR-alpha knockout mice. Antagonism experiments strongly support the engaging of neurosteroidogenic pathway in the increase of LORR duration induced by PEA. This effect disappeared using two inhibitors blocking the key steps of neurosteroids synthesis, aminogluthetimide and finasteride. Moreover, we demonstrated that in brainstem PEA increased the expression of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both involved in neurosteroidogenesis. Accordingly, allopregnanolone (ALLO) levels were in turn higher in brainstem of PEA and pentobarbital treated mice vs pentobarbital alone, as revealed by quantitative analysis using gas chromatography-mass spectrometry. A Our results demonstrate that exogenous administration of PEA, through a PPAR-alpha-dependent mechanism, modulates neurosteroids formation increasing ALLO levels and leading to a positive modulation of GABA(A) receptor. These data further strengthen our previous data on the role of PPAR-alpha in PEA’s actions and could provide a new framework to understand its role in the CNS.

.


From wiki

Have a read en.wikipedia.org/wiki/Steroidogenic_acute_regulatory_protein

1 Like

Let us know how you get on. Good luck mate. Its a safe drug from what i’ve read.

I might give it a go in the future.

Here is some extremely interesting information and could very well explain ihatepropecia702s recovery,

en.wikipedia.org/wiki/Palmitoylethanolamide

en.wikipedia.org/wiki/Peroxisome_proliferator-activated_receptor_alpha

Now if you add that to the above information about how Nystatin inhibits the metabolism Anandamide (AEA), which in studies PEA derivatives also inhibit the metabalism of AEA, you have effectivly done two things inside the body that PEA would do, without using PEA (Activated PPAR-a and inhibited the metabolism of AEA).

Study that show PEA analogues inhibits AEA,

ncbi.nlm.nih.gov/pmc/articles/PMC1621151/


Just some info on the cytochrome P450 side-chain cleavage (P450scc), to go with the StAR info posted above,

en.wikipedia.org/wiki/Cholesterol_side-chain_cleavage_enzyme

Idiopathic Infertility: Effect of Palmitoylethanolamide (a Homologue of Anandamide) on Hyperactivated Sperm Cell Motility and Ca2+ Influx

ABSTRACT

The goal of this study was to examine the effect of palmitoylethanolamide (PEA) on the capacitation process and hyperactivated motility (HA) in idiopathic infertile men. Our data show the effect of PEA on the kinematic parameters of sperm cells from idiopathic infertile men during the capacitation of spermatozoa in vitro, both in the presence and absence of 2.5 nM PEA, a molecule physiologically present in human reproductive tracts. Two groups of sperm cells were identified. In group I (36 ± 14 x 106 cells/mL), PEA significantly increased some motility parameters and HA during capacitation. In group II (58 ± 18 x 106 cells/mL), PEA did not significantly modify motility parameters and HA. Fura 2 AM (acetoxymethyl ester derivative of fura 2) measurements demonstrated that PEA increased external Ca2+ influx (which modulates HA) in group I, while no change was measured in group II. In conclusion, our data indicated that PEA modulated certain physiological sperm functions that are involved in fertilization; in particular, we showed that PEA modulated for HA in men with low sperm kinematic parameters.

andrologyjournal.org/cgi/content/full/26/3/429

Quote from the study,


N-Acylethanolamines in human reproductive fluids.

ncbi.nlm.nih.gov/pubmed/12505702

Sorry two things i should have highlighted earlier,

It appears PEA can also play a role in vitamin d metabolism,

ncbi.nlm.nih.gov/pubmed/21554431

So looking at the p450scc in vitamin d metabolism,

Production of 22-hydroxy metabolites of vitamin d3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells.

Tuckey RC, Li W, Shehabi HZ, Janjetovic Z, Nguyen MN, Kim TK, Chen J, Howell DE, Benson HA, Sweatman T, Baldisseri DM, Slominski A.
Source
School of Biomolecular, Biomedical and Chemical Sciences, M310, The University of Western Australia, Crawley, WA 6009, Australia.

Abstract

Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D(3), producing 20S-hydroxyvitamin D(3) [20(OH)D(3)] and 20S,23-dihydroxyvitamin D(3) [20,23(OH)(2)D(3)] as the major metabolites. These are biologically active, acting as partial vitamin D receptor (VDR) agonists. Minor products include 17-hydroxyvitamin D(3), 17,20-dihydroxyvitamin D(3), and 17,20,23-trihydroxyvitamin D(3). In the current study, we have further analyzed the reaction products from cytochrome P450scc (P450scc) action on vitamin D(3) and have identified two 22-hydroxy derivatives as products, 22-hydroxyvitamin D(3) [22(OH)D(3)] and 20S,22-dihydroxyvitamin D(3) [20,22(OH)(2)D(3)]. The structures of both of these derivatives were determined by NMR. P450scc could convert purified 22(OH)D(3) to 20,22(OH)(2)D(3). The 20,22(OH)(2)D(3) could also be produced from 20(OH)D(3) and was metabolized to a trihydroxyvitamin D(3) product. We compared the biological activities of these new derivatives with those of 20(OH)D(3), 20,23(OH)(2)D(3), and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. 1,25(OH)(2)D(3), 20(OH)D(3), 22(OH)D(3), 20,23(OH)(2)D(3), and 20,22(OH)(2)D(3) significantly inhibited keratinocyte proliferation in a dose-dependent manner. The strongest inducers of involucrin expression (a marker of keratinocyte differentiation) were 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), 20(OH)D(3), and 1,25(OH)(2)D(3), with 22(OH)D(3) having a heterogeneous effect. Little or no stimulation of CYP24 mRNA expression was observed for all the analogs tested except for 1,25(OH)(2)D(3). All the compounds stimulated VDR translocation from the cytoplasm to the nucleus with 22(OH)D(3) and 20,22(OH)(2)D(3) having less effect than 1,25(OH)(2)D(3) and 20(OH)D(3). Thus, we have identified 22(OH)D(3) and 20,22(OH)(2)D(3) as products of CYP11A1 action on vitamin D(3) and shown that, like 20(OH)D(3) and 20,23(OH)(2)D(3), they are active on keratinocytes via the VDR, however, showing a degree of phenotypic heterogeneity in comparison with other P450scc-derived hydroxy metabolites of vitamin D(3).

So this is capable of relieving us of all of our current symptoms and would this have to be taken forever? When will you be giving this a try?

I have some ordered, hopefully its here within a week, if it gets through customs.

If you have a read through the studies i have posted you will get an idea of what it could be capable of.

I will say, that considering finasteride partially inhibited it (PEA), and reading about all its functions in the body via the posted studies, there is strong evidence to suggest that this is the root cause of pfs.


ncbi.nlm.nih.gov/pubmed/18805596

ncbi.nlm.nih.gov/pubmed/14517174

A few more things, all studies that i have read have suggested that PEA has an entourage effect with AEA, so it goes where it goes, does what it does, helps out with actions etc…

mendeley.com/research/palmitoylethanolamide-enhances-anandamide-stimulation-human-vanilloid-vr1-receptors/

So as a guess finasteride has partially inhibited PEA, by what amount i dont know, which has allowed AEA to work alone.

Further studies about AEA,

The endogenous cannabinoid receptor agonist anandamide impairs memory in rats

Mallet, P. E.; Beninger, R. J.

Abstract

Anandamide was recently discovered to be an endogenous substance that acts as a partial agonist at cannabinoid receptors in the central nervous system. Because exogenous cannabinoids such as [DELTA]9-tetrahydrocannabinol ([DELTA]9-THC), the principal psychoactive ingredient of marijuana, have been found to impair memory, we undertook the present study to examine the mnemonic effects of anandamide. Memory was assessed in rats well-trained in a two-component instrumental discrimination task with a conditional discrimination to test reference memory and a delayed nonmatch-to-position to test working memory. Since anandamide has a short metabolic half-life, we examined the mnemonic effects of anandamide (0.0-2.0 mg/kg) in rats pretreated with the protease inhibitor phenylmethylsulfonyl fluoride (2.0 mg/kg), serving to increase the metabolic half-life of anandamide. Under these conditions, a dose-dependent impairment of the nonmatch-to-position, but not the conditional discrimination component, was found, closely resembling that observed following [DELTA]9-THC (0.0-4.0 mg/kg). This is the first report that anandamide impairs memory; results suggest that endogenous cannabinoids may be involved in cognitive processes influencing memory.

journals.lww.com/behaviouralpharm/pages/articleviewer.aspx?year=1996&issue=05000&article=00008&type=abstract

This one is about sheep but its just to show the effect of AEA

High levels of anandamide, an endogenous cannabinoid, block the growth of sheep preimplantation embryos by inducing apoptosis and reversible arrest of cell proliferation.

Turco MY, Matsukawa K, Czernik M, Gasperi V, Battista N, Della Salda L, Scapolo PA, Loi P, Maccarrone M, Ptak G.
Source
Department of Comparative Biomedical Sciences, University of Teramo 64100, Teramo, Italy.

Abstract

BACKGROUND:
The process of implantation is mediated by various molecules, one of which is anandamide (AEA), a lipid signalling ligand belonging to the family of endocannabinoids. AEA exerts its effects on implantation by binding to the Type 1 Cannabinoid Receptor (CB1-R), expressed in both blastocysts and uterus. We wanted to know whether the endocannabinoid signalling system was present also in the sheep reproductive tract and which kind of effect(s) AEA had on the development of sheep blastocysts in vitro.
METHODS:
We analysed the expression and activity of the endocannabinoid system in sheep reproductive tracts and blastocysts. Hatched sheep blastocysts were then exposed to AEA and its effect(s) were determined by TUNEL assay and by measuring the rate of necrosis and 5-bromo-deoxyuridine incorporation.
RESULTS:
We show that the AEA signalling system is present in sheep and that high concentrations of AEA induce apoptosis and inhibit cell proliferation via a CB1-R-dependent mechanism. Indeed, AEA effects were blocked when sheep blastocysts were cultured in the presence of the CB1-R antagonist SR161417A. Moreover, AEA inhibition of cell proliferation was reversible, as arrested embryos resumed a normal growth rate upon AEA removal from the medium.
CONCLUSIONS:
Our results suggest that disturbed regulation of AEA signalling via CB1-R may be associated with pregnancy failure. AEA could lower the quality of blastocysts by inducing apoptosis and inhibiting cell proliferation, thus making them incompetent for implantation.

ncbi.nlm.nih.gov/pubmed/18614613

Can you sum this up in a few paragraphs as to what your thoughts are based on the research you have done?

Thx

  • Palmitoylethanolamide (PEA) is partially inhibited by finasteride, PEA is found in the CNS, most peripheral tissue, and reproductive tract.
  • When administered PEA increased allopregnanalone levels by acting on the Peroxisome proliferator-activated receptor
  • When administered it restored the expression of two proteins involved in neurosteroidogenensis, the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both have a role in formation of steriod hormones in the testis, adrenal cortex.
  • PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxation.
  • PEA has and entourage/regulatory role with anandamide (AEA)
  • It would appear if PEA and AEA become unbalanced to the favor of AEA negative effects will be felt body wide, where as when working together PEA will enhance the effects of AEA.
    -Nystatin reduces AEA levels.

Mew it is clear to me that this has the potential to be the cause of the post finasteride syndrome, a guess at what has happened is that while PEA has been inhibited by finasteride, the AEA levels have become to high, which could potentially suppress PEA and not let it recover back to homeostasis levels.

Have a browse through the studies that i have posted, i have tried to present it in an easily readable way.


Sorry but another study :blush:

Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1

Abstract

Anandamide triggers various cellular activities by binding to cannabinboid (CB1/CB2) receptors or vanilloid receptor 1 (VR1). However, the role of these receptors in anandamide-induced apoptosis remains largely unknown. Here, we show that SR141716A, a specific inhibitor of cannabinoid receptor (CB1-R), did not block anandamide-induced cell death in endogenously CB1-R expressing cells. In addition, CB1-R-lacking Chinese hamster ovary (CHO) cells underwent cell death after anandamide treatment. SR144528, a specific inhibitor of CB2-R also failed to block anandamide-induced cell death in HL-60 cells. Capsazepine, a specific antagonist of VR1 could not prevent anandamide-induced cell death in constitutively and endogenously VR1 expressing PC12 cells. Moreover, anandamide noticeably triggered cell death in VR1-lacking human embryonic kidney (HEK) cells. In contrast, methyl-# cyclodextrin (MCD), a membrane cholesterol depletor, completely blocked anandamide-induced cell death in a variety of cells, including PC12, C6, Neuro-2a, CHO, HEK, SMC, Jurkat and HL-60 cells. MCD also blocked anandamide-induced superoxide generation, phosphatidyl serine exposure and p38 MAPK/JNK activation. Thus, our data imply a novel role for of membrane lipid rafts in anandamide-induced cell death.

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