I’ve been reading about progesterone and post translational mechanisms in particular these articles:
ncbi.nlm.nih.gov/pubmed/15669543
ncbi.nlm.nih.gov/pubmed/22872761
There has been a lot of mixed response to progesterone from people have tried to from people claiming potential recoveries (alongside testosterone boosters) and people who have had little response from it (good or bad) and lastly people like robbo who claim it made things much worse.
I’m going to write a summary of what we know from science about the effects of progesterone in men as stated in the review article above.
[Size=4]Progesterone[/size]
Pregnenolone is the precursor of progesterone catalysed by 3 beta hydroxysteroid dehydrogenase. Progesterone has three major metabolites: 17 alpha OH-P (leads to cortisol production and androstenedione and dehydroepiandrosterone), desoxycorticosterone, and pregnanediol. Progesterone is also a precursor to neurosteroids.
DHEA oddly increases progesterone which is upstream metabolism (in a study on only 2 men). Progesterone in men is made in the Leydig cells of the testicles and adrenal gland and is then secreted into the circulatory system. Normal levels in men are thought to be 0.13-0.97 ng/ml. Levels themselves do not seem to change as people get older.
Progesterone acts via two progesterone receptors - PR-A and PR-B. These actions exert genomic effects which happen slowly over time. These genomic actions include possibly contributing to tumours in the CNS, gonadotrophin blockage, immunosuppression, contributing to weight gain, possibly contributing to prostate problems.
However, progesterone has been found to have rapid effects incompatible with normal genomic effects hence these are called non genomic effects.
These non genomic which can happen quickly within days include supporting sperm capacitation, reducing LH receptor expression and subsequent decrease of testosterone biosynthesis, increased PR concentrations in the prostate, interactions with the GABA receptor via neurosteroids, actions in adipose tissue and kidney.
Progesterone inhibits the function of human macrophages and T lymphocytes within physiological concentrations - therefore a possible immunosuppressant. However, progesterone is thought to be an anti-inflammatory and it is unclear how. High dose progesterone infusions in men have shown it does not appear to have any systemic anti-glucorticoid action - does not change ACTH or cortisol levels.
It is conceivable a local increase in progesterone levels in the testicles may have a detrimental effect on Leydig cell function. Incubation of Leydig cells with progesterone inhibits the expression of the promoter gene for the LH receptor gene - reducing its overall expression therefore resistant to LH action and testosterone production. Progesterone antagonists such as mifepristone seem to increase testosterone production.
Progestins in the prostate inhibit the the cellular uptake of testosterone and the binding of androgen to the receptor and they decrease the level of androgen receptors.
Another risk of prolonged progesterone therapy is the possibility of promoting the growth of benign intracranial meningiomas (brain tumours) as reported in one case study. Neurofibromas do express PR receptors.
Progesterone, pregnenolone, DHEA are present in higher concentrations in the the brain than in blood and are synthesised by various brain cells. These are called neurosteroids and convert to other neurosteroids such as allopregnanolone via 5 alpha reductase type 2. The gene expression of 5 alpha reductase type 2 is transcriptionally regulated by progesterone. Neurosteroids affect neuroblasts and astrocytes. Neurosteroids modify neuronal physiology and also modulate ligand gated ion channels via non genomic mechanisms - such as in the modulation of GABA receptors. Progesterone is rapidly converted into GABAergic neuroactive steroids in vivo. They can produce benzodiazepine like sleep EEG profiles in rats and humans. In low concentrations regulate learning and memory. Progesterone is neuroprotective and is being investigated in traumatic brain injury as well as peripheral nerve injury and spinal cord injury. Blocking progesterone actions impairs demyelination of regenerating axons when a nerve is damaged. Administration of progesterone promotes the formation of new myelin sheaths. Systemic progesterone administration resulted in partial reversal of age associated decline in CNS demyelination following toxin induced demyelination in male rats. Neuroactive steroids may be involved in the treatment of depression and anxiety.
Deregulation of allopregnanolone and 3 alpha, 5 alpha TH DOC has been found in depression. Neurosteroid levels normalise after treatment with SSRIs. Finasteride was shown to diminish the anti convulsant effects of allopregnanolone. Neurosteroids increase non REM sleep. Neurosteroid analogs are being looked into due to the negative genomic actions of progesterone.
Progesterone reduces mating activities in rats. At very high doses it is given to male sex offenders in the USA - reducing sexual activity. The down regulation of sex hormone receptors including PR do contribute to erectile dysfunction. Testosterone and sexual experience increase the level of plasma membrane binding sites for progesterone in the brain.
Progesterone has possibly useful respiratory actions too which i won’t go into.
In one experiment a single dose of depot progestin norethindorne enanthate in seven healthy white men aged between 28-38 lead to significant suppression of serum free and total testosterone and of serum 17 beta estradiol on day 14 post injection.
Progesterone does act as an antiglucorticoid in adipose tissue in vivo blocking the effects of dexamethasone. Likely due through non genomic mechanism. Progesterone has an anti-anabolic effect on muscle size even when combined with testosterone. However when combined with resistance exercise total muscle strength did significantly increase.
[Size=4]Androgen receptor
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In the review article by Coffrey and Robson they go into full detail about mechanisms by which the androgen receptor is regulated. Again i’m going to summarise some of its findings.
ncbi.nlm.nih.gov/pubmed/22872761
To figure out how to treat our problem we need to understand what is happening at the AR level and by what mechanism things are silenced.
In brief post translational mechanism processes include acetylation, phosphorylation, sumoylation, ubiquitination and methylation.
AR acetylation. When HDAC inhibitor trichostatin A (TSA) was in the presence of DHT transcription, chromatin remodelling and AR levels were enhanced. When AR cannot be acetylated TSA can no longer activate the AR and even co-activation through SRC1, p300, PCAF, Ubc9, Tip60 does not help - this leads to reduced recruitment of AREs. (androgen responsive elements).
Acetylation is a dynamic process that is reversed by HDAC enzymes (these down regulate AR activity). So acetylation up regulates recruitment of AREs.
Acetylation of AR is induced by androgen stimulation. There are other things that influence the levels of acetylation though. Bombesin through p300 and Src can enhance it. IL4 also activates the AR in the absence of androgens via elevation of CBP/p300 to enhance acetylation. The role of co-regulators and their post translational mechanisms also need to be studied in our condition. p300 acetylates B- catinen regulating its interaction with TCF and the AR to result in enhanced receptor transcriptional activity to regulate a subset of genes.
HAT inhibitors are used to inhibit acetylation. These include rosaceae, resveratrol, procyanidin B3, green tea, allspice. Curcumin affects p300 too leading to downregulation of androgen responsive genes. How have people responded to these things???
All spice - inhibits p300 and CBP activity, rosacea suppresses ligand mediated activation, enhances effects of AR antagonists, resveratrol - reduced nuclear AR, reduced DNA binding, reduced AR protein levels, green tea - reduced AR dependent gene transcription.
Methylation of histone proteins can also regulate AR activity. Methylation and demethylation are key in the initiation and regulation of transcription. Set9 mediated methylation is a transcriptional activator. Only two studies describe direct methylation of the AR and demethylation has yet to be reported. There is much scope for investigation here. It admittedly is in its infancy and may prove to be very important.
Phosphorylation of the AR is a complex component of the signalling pathway. Increasing androgens results in stimulation of phosphorylation. AR is phosphorylated under conditions of androgen depletion. When phosphorylated it allows ligand binding but then undergoes further phosphorlyation upon androgen stimulation. Phosphorylated AR can determine whether or not AR ligands perform as agonists or antagonists. There are numerous phosphorylation sites including Ser16, Ser81, Ser213, Ser578, Tyr267, Tyr534. Interestingly IGF1 is a stimulator of Ser650 and Ser213 and DHT is of Ser213 also. Some of these processes occur in the nucleus and others in the cytoplasm.
Protein kinase A (PKA) and PKC were investigated as AR kinases as their activation results in enhanced AR activity in the presence of ligand. This activation is not a result of increased AR levels or increased DNA binding capacity indicating the effect of PKA on AR is indirect. Dephosphorlyation stimulated by forskolin treatment resulted in decreased AR transcriptional activity and reduced binding. Increasing androgens increases the phosphorylated form. In the absence of androgens PKA activated the AR - a consequence of increased nuclear AR.
Phosphorylation of the AR is a reversible process. Currently only two protein phosphates have been described to interact and dephosphorylate the AR. Protein phosphatase 2A acts and results in enhanced AR stability and transcriptional activity. PP1 has been shown to dephosphorylate Ser650 resulting in enhanced AR levels, transcriptional activity and nuclear localisation. Sr650 and Ser662 can be desphosphorylated in response to PKA stimulation by forskolin resulting in decreased AR transcriptional activity and reduced ligand binding. Bicalutamide can also reduced AR-P.
Some anti-androgens can enhance AR nuclear levels and induce AR-P levels. Much again needs to be studied here.
Ubiquitination is an important mechanism by which the cell regulates the turnover of proteins and also functions as a signalling moiety to affect functional outcomes. Ubiquitination of AR on the promoters of AR responsive genes is thought to function to clear the promoter ready for subsequent rounds of transcription. Numerous proteins regulate this. HSP27 being one of them. Phosphorylation interacts with this process too as it is needed for some ubiquitination to occur.
Sumoylation is the process is another modifier. Thoguht to determine cellular localisation and in some cases regulate transcriptional activity. It also might be a protective mechanism to prevent structural alterations to proteins to cellular stress. SUMO2 and SUMO3 strongly enhance AR transcriptional activity. Again it is a reversible process achieved by a family of SUMO proteases of which there are 6.
Some of the above processes interact with each other. Meythlation and acetylation might indeed cross talk. Acetylation should precede methylation upon stimulation with androgens. Deacteylation is required also before methylation. SIRT1 is a deacetylase enzyme that can repress DHT mediated AR expression by binding to and deacetylating AR.
Where we are at!
Ok so how can we relate all this to our situation. So far from my understanding we know that:
- Androgen receptors are paradoxically overexpressed in penile tissue. Finasteride has been shown to cause overexpression of the receptor whilst on it.
- We don’t appear to react normally to androgens in terms of function. Some people respond a little to increase androgens but a lot do not even when increased to supra physiological levels. This is likely epigenetic in origin and most likely due to one of the post translational mechanisms above.
- Lower levels of neurosteroids have been found in our CNS.
Our symptoms are roughly divided into sexual and mental ones. From personal experience i have both to some extent. In general whenever i increase androgens via tongkat or other herbal stuff mental function worsens. Sometimes when mentally i’m ok sexually is dead as door post. This is not surprising as shown below.
Increasing testosterone also reduces neurosteroids! journals.lww.com/neuroreport/Abs … by.16.aspx
Each of us with PFS have been affected slightly differently. Some with more mental problems (low mood, anxiety, vision issues, brain fog) and others with more androgen related (low libido, ED, shrunken genitalia, fatigue, inability to build muscle easily, drier skin).
I think the androgen related problem is the tough nut to crack. The working theory put forward by awor which i think is on the right lines is that we have persistent androgen hypersensitivity with post translational silencing of androgen responsive genes. Some mechanisms suggest that increasing androgens further should reduce AR mRNA and the overexpression and potentially lift any silencing downstream but we might just lack that mechanism hence we are in this mess in the first place. Some people like CDnuts have recovered by a steady persistent raised testosterone level.
Research hopefully will shine light on where along the pathway our problem is. The most important thing to note is that none of these mechanisms are permanent. As for progesterone it is easy to understand how it can help mentally and people report it acting quickly suggesting that the positive effects happen due to non genomic reasons. It also seems to reduce androgen receptor expression which could be the reason some people improved sexually on it.
That being said it is an anti androgen, will reduce libido and if take long term can have negative effects. I would not apply it directly to the testicles though as local increase in progesterone might make you less responsive to LH. We don’t know how it interacts with the androgen receptor and its modifications. It may well be helpful to some for its neurosteroid boost and effect on androgen receptors.
If we understand these two pathways I believe we will find a way out of this.