RP Email Advice Comment: 5-Alpha Dihydroprogesterone

[goodandevil]

@Koveras I guess one has to be careful not to focus on one part of the endocrine system as it's all related and can probably only be understood by taking a step back. If 5 dihydroprogesterone affects one pituitary characteristic (estrogen "recepors"), then it makes sense the whole gland would be similarly affected, possibly for better, possibly for worse. And also too, as you're showing, the pituitary hormone alone doesn't indicate the degree of responsiveness in the terminal tissue, which seems to depend on many factors. I wonder of roddy has thought about all this it can be tempting to adopt the mainstream view of one hormone for one function but clearly they work together and influence each other.

 

[haidut]

Expression of steroid 5α-reductase isozymes in prostate of adult rats after environmental stress.
Sánchez P1, Torres JM, Castro B, Olmo A, del Moral RG, Ortega E.

The elevated incidence of prostate cancer and benign prostatic hypertrophy is a cause of increasing public health concern in the Western world. The normal and pathological growth of the prostate are both dependent on stimulation by dihydrotestosterone, which is synthesized from circulating testosterone by two 5α-reductase (5α-R) isozymes, 5α-reductase type 1 (5α-R1) and 5α-reductase type 2 (5α-R2). Both isozymes have been implicated in prostate disease. We used quantitative RT-PCR and immunohistochemistry, respectively, to quantify mRNA and protein levels of 5α-R isozymes in the ventral prostate of adult rats under environmental stress conditions analogous to those found in some common workplace situations, i.e. artificial light, excessive heat, and the sensation of immobility in a small space. Transcription and expression levels of both 5α-R isozymes were significantly higher in environmentally stressed rats than in unstressed rats. Increased 5α-R isozyme levels may play a role in the development or maintenance of prostate disease. Further research is warranted to explore these effects of environmental stress on human health and their implications for environmental and occupational health policies.


Prolactin effect on the permeability of human benign hyperplastic prostate to testosterone
http://www.ncbi.nlm.nih.gov/pubmed/2453860

"While it has been known for over 30 years that prolactin (Prl) synergizes with androgen in the support and stimulation of prostatic growth and metabolism, the evidence that this is accomplished through increasing access of the steroid to the cellular machinery of the gland has arisen only since about 1970. There is widespread uncertainty as to how the Prl effect takes place: by 1) increasing the free steroid concentration in the blood; 2) facilitating the uptake of protein-bound androgen; 3) increasing, by metabolism or receptor-binding, the concentration gradient that can support passive diffusion of the steroid across the plasma membrane; or 4) modification of the fluidity of the membrane itself to increase the solubility of the steroid in the lipoprotein and, thus, the ease of penetration of the cell. The present study attempted to learn if Prl is an effective stimulus of androgen uptake when the first three options are not operative. Using an equilibrium exchange procedure to track the uptake of [17 alpha-3H]-testosterone ([17 alpha-3H]-T) into minced benign hyperplastic human prostate tissue and the irreversible metabolism of the entering steroid to [17 alpha-3H]-dihydrotestosterone [17 alpha-3H]-DHT, it was found that the rate of production of the 5 alpha-reduced metabolite, during a 1-hr incubation in vitro, was directly proportional to the concentration of ovine Prl over the dose range of 0-160 ng/ml. The clinical significance of Prl mediation of steroid uptake is discussed, and suggestions are made as to how the Prl might alter the permeability of the plasma membrane."


J Physiol Biochem. 2013 Mar;69(1):133-40. doi: 10.1007/s13105-012-0197-4. Epub 2012 Jul 18.
Effects of metoclopramide on mRNA levels of steroid 5α-reductase isozymes in prostate of adult rats.
Sánchez P1, Torres JM, Castro B, Frías JF, Ortega E.

The rising incidence of prostate cancer and benign prostatic hypertrophy in the Western world is a cause of increasing public health concern. The most active androgen in the prostate is 5α-dihydrotestosterone obtained from testosterone (T) by the enzyme 5α-reductase (5α-R), expressed in the prostate as two isozymes, 5α-R1 and 5α-R2. These isozymes are involved in the growth and development of normal prostate and in the onset and progression of prostate disease. Besides androgens, prolactin (PRL) may also play a role, although it is not clear whether its effects on the prostate are in synergism with or independent of those of androgens. We previously demonstrated that sulpiride, an inductor of hyperprolactinemia, increased mRNA levels of 5α-R isozymes in prostate of adult rat. We hypothesized a possible interrelationship between PRL levels and 5α-R, although the effects of sulpiride per se cannot be ruled out. In the present study, one-step quantitative reverse transcription polymerase chain reaction coupled with laser-induced fluorescence capillary electrophoresis was used to quantify mRNA levels of both 5α-R isozymes in prostate of adult rat after administration of metoclopramide (MTC), another inductor of PRL secretion. With the administration regimens studied, MTC produced an increase in prostate weight and mRNA levels of 5α-R1 and 5α-R2 in adult rats. Given our finding that MTC per se or MTC-induced hyperprolactinemia modifies prostate disease-related parameters in animals with reduced plasma T levels, further investigation is warranted into the possibility that MTC use by aging males may increase their risk of prostate disease.

Effects of sulpiride on mRNA levels of steroid 5alpha-reductase isozymes in prostate of adult rats. - PubMed - NCBI

"Prolactin (PRL) is implicated in prostate growth and in the development and regulation of benign prostatic hypertrophy (BPH) and prostate cancer (PCa). PRL may exert its effects on prostate in synergism with androgens. The most active androgen in the prostate is the 5alpha-dihydrotestosterone (DHT) obtained from testosterone by the 5alpha-reductase (5alpha-R) enzyme, which is expressed in the prostate as two isozymes, 5alpha-R1 and 5alpha-R2. In this study, sulpiride, a prolactin-secretion inductor, was administered to male rats. mRNA levels of 5alpha-R1 and 5alpha-R2 were measured in prostate of controls and sulpiride-treated rats, using one-step quantitative RT-PCR coupled with laser-induced fluorescence capillary electrophoresis (LIF-CE). Results demonstrated that sulpiride-induced hyperprolactinemia is associated with an increase in mRNA levels of both 5alpha-R1 and 5alpha-R2 in prostate of adult rats. Although a direct effect of sulpiride on prostate gland cannot be ruled out, hyperprolactinemia may be a factor to be considered in aging males, in whom prostatic diseases such as BPH and PCa are more frequent.”

Effects of sulpiride on prolactin and mRNA levels of steroid 5alpha-reductase isozymes in adult rat brain. - PubMed - NCBI

"Prolactin (PRL) promotes maternal behavior (MB), a complex pattern of behavior aimed at maximizing offspring survival. 3alpha,5alpha-reduced neurosteroids may also regulate MB. Indeed, PRL, 3alpha,5alpha-reduced neurosteroids, and 5alpha-reductase (5alpha-R), the key enzyme in the biosynthesis of these neuroactive steroids, are all increased in stress situations These facts led us to hypothesize a possible interrelation between PRL levels and 5alpha-R. In the present study we quantified mRNA levels of both 5alpha-R isozymes in prefrontal cortex of male and female rats after administration of sulpiride, an inductor of PRL secretion. Our results demonstrated that mRNA levels of both 5alpha-R isozymes were significantly increased in male and female rats by sulpiride, directly or via sulpiride-induced hyperprolactinemia. Since 3alpha,5alpha-reduced neurosteroids and PRL exert anxiolytic effects in response to stress, these molecules and 5alpha-R may possibly participate in a common pathway of significant adaptation to stress situations.”

Effects of testosterone and prolactin on rat prostatic weight, 5alpha-reductase, and arginase. - PubMed - NCBI

"Prostatic weights, 5alpha-reductase, and arginase activities were utilized as indexes for the effects of prolactin in short-term experiments in intact, hypophysectomized or castrated rats. Experiments were performed in which a dose-related response in the above parameters was obtained with testosterone administration in castrated mature and immature rats in order to evaluate the effects of simultaneously administered prolactin. This approach was necessitated by the failure of prolactin alone to affect the parameters listed in intact, castrated or hypophysectomized rats. It was shown that ovine prolactin may have an enhancing effect on the prostatic weight, 5alpha-reductase, and arginase activities, but that this effect is neither consistent nor striking when compared to that of testosterone.. Nevertheless, it is still possible that the long-term effects of prolactin, even if they are only of an enhancing quality, may play an important role in normal prostatic physiology and in abnormal states.”

Prolactin influences upon androgen action in male accessory sex organs. - PubMed - NCBI

"The hormones of the pituitary gland are capable of directly influencing the function of male accessory sex organs. Among these hormones, prolactin in particular has been observed to enhance consistently the effects of androgens in the prostate gland and/or the seminal vesicles of rats, mice, and guinea pigs as well as in the accessory sex organs of other species. Prolactin-mediated augmentation of testosterone's effects upon these tissues is related primarily to the growth-promoting influences of this steroid. However, under certain experimental conditions, the androgen-dependent production of secretions by these organs has also been enhanced by prolactin treatment. Studies in the mouse have indicated that prolactin primarily enhances the proliferative phase of androgen action in male accessory sex tissues. Testosterone stimulation of RNA synthesis was unaffected by simultaneous administration of prolactin. The mechanism by which prolactin causes enhanced androgen responses in the prostate gland and seminal vesicles is not well understood. It would appear, however, that prolactin neither stimulates increased accumulation of androgen into the accessory sex organs, nor does it enhance the conversion of testosterone to the more "active" androgen, dihydrotestosterone. The effects of prolactin on these tissues are, however, dependent upon the presence of dihydrotestosterone. Uncertain, at present, are the possible effects of prolactin on the binding or retention of androgens (dihydrotestosterone?) in the prostate gland or in the seminal vesicles. There is evidence that hypophysectomy reduces the nuclear binding of dihydrotestosterone in the cells of the prostate gland. Perhaps prolactin is a pituitary factor(s) which is important in regulating nuclear binding of dihydrotestosterone in male accessory sex organs. The direct influences of prolactin upon androgen action in the cells of the accessory sex organs may involve several sites of action (Figure 2). For example, it is currently understood that when testosterone enters the cell cytoplasm it is subsequently converted to the more "active" androgen, dihydrotestosterone (DHT), by reduction at the 5alpha position. Dihydrotestosterone is then either bound to a cytoplasmic "receptor" protein (Rc) or is further metabolized to either 5alpha-androstane-3alpha,17beta-diol or 5alpha-androstane-3beta,17beta-diol (DIOL). The binding of DHT to its cytoplasmic receptor protein results in translocation of the steroid-receptor complex into the nucleus where presumably the complex dissociates and DHT exerts its androgenic effects. The transport of DHT to the nucleus can also result from the conversion of testosterone to DHT by nuclear membrane-bound 5alpha-reductase. Prolactin augmentation of DHT effects is envisioned as resulting from interaction of prolactin with its receptor, which due to the large size of the prolactin molecule is probably located in or on the plasma membrane…"

I think the increase in 5-AR by prolactin is to keep the stress hormones in check. Prolactin elevates ACTH and cortisol, and estrogen.5-AR activity is absolutely crucial for the degradation of cortisol and the increase synthesis of DHT may server to balance the increase in estrogen and prolactin, as DHT opposes both hormones. Ultimately, it is all due to stress but DHT is there to oppose the bad guys. Almost like HDL being raised by toxins such as alcohol, radiation and endotoxin.

 

[haidut]

Absolutely


Prolactin has a direct effect on adrenal androgen secretion.

http://www.ncbi.nlm.nih.gov/pubmed/6090494


"The role of PRL in the secretion of androgens by the adrenal glands was investigated in vivo and in vitro. In women with hyperprolactinemia whose pituitary-adrenal function was normal, there was significant correlation between serum PRL and dehydroepiandrosterone sulfate [(DHEA-S) gamma = 0.48, P less than 0.05, n = 34] and DHEA (gamma = 0.50, P less than 0.05, n = 34), but not with androstenedione. Long term administration of sulpiride to normal women increased both serum PRL and DHEA-S, whereas acute elevation of PRL after a single iv dose of domperidone had no influence on the serum DHEA-S levels. Monolayer cultures of human adrenal cells were used in order to study the direct effect of PRL on adrenal androgen secretion. The daily secretion of DHEA-S, DHEA, androstenedione, and cortisol was determined. In the absence of ACTH, PRL had no effect on steroid secretion in a 7-day culture period. In the presence of ACTH, there was a daily increase in the secretion of steroids. PRL, when added in combination with ACTH, potentiated the effect of ACTH on DHEA-S and DHEA but not on androstenedione and cortisol secretion on the seventh day in culture. These results indicate that PRL has a direct synergistic effect with ACTH on adrenal cells to increase adrenal androgen release. Increases in DHEA-S and DHEA but not androstenedione in vitro and correlation between serum PRL and DHEA-S and DHEA but not androstenedione in women with hyperprolactinemia suggest that the synergistic effect of PRL on adrenal androgen secretion may result from partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase.”

Yes, for a good reason. Prolactin is a stress hormone, so it is cortisol, ACTH and CRH. They all stimulate the secretion of pregnenolone, progesterone and DHEA. Probably as a defensive mechanism to keep the bad influence in check. Estrogen is unique in this respect as it lowers DHEA secretion probably as a negative feedback mechanism as DHEA can easily turn into more estrogen. The suppression from taking T works via the same mechanism - increased estrogen from aromatase will inhibit further synthesis of T as a possible source of more estrogens. So, the initial stress response increases all steroid synthesis but as estrogen keeps climbing the negative feedback mechanism kicks in and then DHEA, pregnenolone and progesterone go down and there is nothing lest to oppose estrogen and cortisol. So, in that sense I think estrogen is the true "***t storm" hormone - it can deactivate the very mechanisms that are in place to protect against. So, I have yet to see a situation where suppressing estrogen is a bad idea.

 

[Dante]

Yes, for a good reason. Prolactin is a stress hormone, so it is cortisol, ACTH and CRH. They all stimulate the secretion of pregnenolone, progesterone and DHEA. Probably as a defensive mechanism to keep the bad influence in check. Estrogen is unique in this respect as it lowers DHEA secretion probably as a negative feedback mechanism as DHEA can easily turn into more estrogen. The suppression from taking T works via the same mechanism - increased estrogen from aromatase will inhibit further synthesis of T as a possible source of more estrogens. So, the initial stress response increases all steroid synthesis but as estrogen keeps climbing the negative feedback mechanism kicks in and then DHEA, pregnenolone and progesterone go down and there is nothing lest to oppose estrogen and cortisol. So, in that sense I think estrogen is the true "***t storm" hormone - it can deactivate the very mechanisms that are in place to protect against. So, I have yet to see a situation where suppressing estrogen is a bad idea.

Are you aware of any clinical trial that is using DHT as a main line treatment for prostate cancer ? Regarding estrogen , don't you think that it has some beneficial action in males in nominal/small amounts ? Slowing osteoclasts is one that comes to mind. Perhaps somewhere in brain it might have it's use too but the technology is not that developed to find that out. People who reduce estrogen too much report problems

 

[haidut]

Are you aware of any clinical trial that is using DHT as a main line treatment for prostate cancer ? Regarding estrogen , don't you think that it has some beneficial action in males in nominal/small amounts ? Slowing osteoclasts is one that comes to mind. Perhaps somewhere in brain it might have it's use too but the technology is not that developed to find that out. People who reduce estrogen too much report problems

Yes, some estrogen is absolutely needed for male libido and maybe even would healing. I think the inhibition would be beneficial if you have high tissue estrogen, as confirmed by blood tests for prolactin and estrone sulfate (E1S). It is chronically elevated estrogen that is the problem, not acute elevations to meet needs for tissue growth.
I don't think there is a human study (yet) with DHT for prostate cancer but I posted one with testosterone for metastatic and castration-resistant prostate cancer, which is considered terminal.

 

[Wagner83]

I think the increase in 5-AR by prolactin is to keep the stress hormones in check. Prolactin elevates ACTH and cortisol, and estrogen.5-AR activity is absolutely crucial for the degradation of cortisol and the increase synthesis of DHT may server to balance the increase in estrogen and prolactin, as DHT opposes both hormones. Ultimately, it is all due to stress but DHT is there to oppose the bad guys. Almost like HDL being raised by toxins such as alcohol, radiation and endotoxin.

Any connection between this and certain forms of strength work outs increasing 5ar/dht levels ?

 

[haidut]

Any connection between this and certain forms of strength work outs increasing 5ar/dht levels ?

Strength training has been shown to increase muscle levels of DHT and some studies claim this is the reason for the beneficial effects of exercise (increase of DHT). I posted some studies by a group that showed lower dose DHEA (10mg-15mg daily for a human) had the same effects as exercise on muscle DHT levels.
https://raypeatforum.com/community/...s-effects-as-exercise-by-increasing-dht.6018/
Low dose DHEA restores insulin sensitivity by increasing DHT

 

[Pointless]

The study was not meant to discredit Ray's studies. User @Makrosky asked for it and I simply posted it. I am actually seriously considering cancelling the 5a-DHP until more is known about it. It is indeed only one study and I am not aware of any others that have verified its claims, even though quite a few recent studies (circa 2015 - 2016) cite it. Of course that does not prove anything.
Anyways, I think we are making this into a bigger deal than it is. One study does not prove anything until it is replicated independently.

You might want to consider editing the post that the link on the website leads to, to include the cancer studies so that people know the risk.

Something a bit more on the constructive side, are there any Peaty substances that might inhibit the MAPK signalling pathyway that 5a-DHP activates? I found this study on DHT and MAPK, but it doesn't specifically mention what the effect on MAPK is. In fact I think MAPK is like a functional type of signalling proteins, not a specific protein. The whole thing is beyond my level of expertise.

Dihydrotestosterone interacts with EGFR/MAPK signalling and modulates EGFR levels in androgen receptor-positive LNCaP prostate cancer cells. - PubMed - NCBI

 

[haidut]

You might want to consider editing the post that the link on the website leads to, to include the cancer studies so that people know the risk.

Something a bit more on the constructive side, are there any Peaty substances that might inhibit the MAPK signalling pathyway that 5a-DHP activates? I found this study on DHT and MAPK, but it doesn't specifically mention what the effect on MAPK is. In fact I think MAPK is like a functional type of signalling proteins, not a specific protein. The whole thing is beyond my level of expertise.

Dihydrotestosterone interacts with EGFR/MAPK signalling and modulates EGFR levels in androgen receptor-positive LNCaP prostate cancer cells. - PubMed - NCBI

You mean for 5a-DHP? I am actually about to pull the plug on that supplement until we know more. I may replace it with 20a-DHP, which is a known aromatase inhibitor.

 

[dookie]

Yes, for a good reason. Prolactin is a stress hormone, so it is cortisol, ACTH and CRH. They all stimulate the secretion of pregnenolone, progesterone and DHEA. Probably as a defensive mechanism to keep the bad influence in check. Estrogen is unique in this respect as it lowers DHEA secretion probably as a negative feedback mechanism as DHEA can easily turn into more estrogen. The suppression from taking T works via the same mechanism - increased estrogen from aromatase will inhibit further synthesis of T as a possible source of more estrogens. So, the initial stress response increases all steroid synthesis but as estrogen keeps climbing the negative feedback mechanism kicks in and then DHEA, pregnenolone and progesterone go down and there is nothing lest to oppose estrogen and cortisol. So, in that sense I think estrogen is the true "***t storm" hormone - it can deactivate the very mechanisms that are in place to protect against. So, I have yet to see a situation where suppressing estrogen is a bad idea.

Estrogen lowers DHEA? I thought it was associated with high DHEA levels. Like in PCOS, etc

 

[haidut]

Estrogen lowers DHEA? I thought it was associated with high DHEA levels. Like in PCOS, etc

In some cases. It is quite common for people with hypothyroidism to have high cortisol and estrogen and low DHEA and other androgens. One study I saw recently said it was a negative feedback cycle to avoid creating more estrogen. Not sure if the study was simply making a generalization from the way T causes shutdown when taken in high doses (i.e. through aromatization to estrogen).

 

[skycop00]

Disregard..

 

[TubZy]

You mean for 5a-DHP? I am actually about to pull the plug on that supplement until we know more. I may replace it with 20a-DHP, which is a known aromatase inhibitor.

Is this still the case?

 

[haidut]

Is this still the case?

I am looking into 20a-DHP. It's not something I can decide on overnight. There are a lot of studies to go through. Even a madman like me can't handle them in a few days

 

[TubZy]

I am looking into 20a-DHP. It's not something I can decide on overnight. There are a lot of studies to go through. Even a madman like me can't handle them in a few days :)

Understood Master Haidut, may the force be with you in your new discoveries

 

[bruschi11]

@haidut would 20a-DHP have these similar allopreg pathway effects as 5a-dhp? Honestly this has legitimately improved my post finasteride issues so far by at least 50%. I only came off of it a month ago and my endocrine system was going into a downward spiral as I noted before here.

The last 4 days on this has truly done something amazing. I added actual preg cream last night to this protocol and this morning with low dose DHEA (5mg) and i feel like I'm actually filling the pathways without the super fast preg---> cortisol conversion that was taking place.

Sure blood pressure is still a bit high, but definitely dropping.

I feel like this could and should be marketed as both a post fin or even pre-fin product. Something you'd advise someone if they are going to take the risk with fin that you need to take this with it. Kind of like TRT with HCG or arimidex. But even more needed in this case... Trust me.

The anxiety spirals I was going through seem to have come to an end knock on wood. We will see but this product is something special that has allowed my cortisol production stream to get back on track.

 

[NathanK]

Absolutely


Prolactin has a direct effect on adrenal androgen secretion.

Prolactin has a direct effect on adrenal androgen secretion. - PubMed - NCBI


"The role of PRL in the secretion of androgens by the adrenal glands was investigated in vivo and in vitro. In women with hyperprolactinemia whose pituitary-adrenal function was normal, there was significant correlation between serum PRL and dehydroepiandrosterone sulfate [(DHEA-S) gamma = 0.48, P less than 0.05, n = 34] and DHEA (gamma = 0.50, P less than 0.05, n = 34), but not with androstenedione. Long term administration of sulpiride to normal women increased both serum PRL and DHEA-S, whereas acute elevation of PRL after a single iv dose of domperidone had no influence on the serum DHEA-S levels. Monolayer cultures of human adrenal cells were used in order to study the direct effect of PRL on adrenal androgen secretion. The daily secretion of DHEA-S, DHEA, androstenedione, and cortisol was determined. In the absence of ACTH, PRL had no effect on steroid secretion in a 7-day culture period. In the presence of ACTH, there was a daily increase in the secretion of steroids. PRL, when added in combination with ACTH, potentiated the effect of ACTH on DHEA-S and DHEA but not on androstenedione and cortisol secretion on the seventh day in culture. These results indicate that PRL has a direct synergistic effect with ACTH on adrenal cells to increase adrenal androgen release. Increases in DHEA-S and DHEA but not androstenedione in vitro and correlation between serum PRL and DHEA-S and DHEA but not androstenedione in women with hyperprolactinemia suggest that the synergistic effect of PRL on adrenal androgen secretion may result from partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase.”

Thank you for these, K.

Excellent thread discussion that followed as well

 

[Risingfire]

I am looking into 20a-DHP. It's not something I can decide on overnight. There are a lot of studies to go through. Even a madman like me can't handle them in a few days

Are you still considering this?

 

[haidut]

Are you still considering this?

Not really, as 6-keto should be just as good (if not even better) as an aromatase inhibitor.

 

[golder]

You mean for 5a-DHP? I am actually about to pull the plug on that supplement until we know more. I may replace it with 20a-DHP, which is a known aromatase inhibitor.

Out of curiosity could you let us know what happened to this decision, and what information tipped the balance in not doing so?