RP Email Advice Comment: 5-Alpha Dihydroprogesterone

[raypeatclips]

@haidut I was online when you replied so sent your response pretty much straight away, so didn't get the edit unfortunately. No second response from Peat yet.

 

[X3CyO]

Soooo. To play it safe, just increase the bodies cholesterol synthesis and processing instead of using downstream chemicals.


I think this is just the other side of spectrum though; too much anabolism. Just as there can be too much catabolism; its best to just stick to the middle ground.


Im almost certain if someone were to obtain issues from this compound, then ceasing to use it would resolve issues if it really is just the opposite of the spectrum.

Of course this is just a hypothesis.

 

[haidut]

@haidut I was online when you replied so sent your response pretty much straight away, so didn't get the edit unfortunately. No second response from Peat yet.

No problem, it's probably OK that way too. If he does responds or you get a chance to ask him later, I would be very interested to hear his thoughts on the progesterone to breast cancer connection. Giving progesterone to humans raises 5a-DHP and allopregnanolone as shown by the human studies. Does that mean progesterone may be inappropriate in the context of breast cancer unless administered (God forbid) with a 5-AR inhibitor? That study clearly showed that progesterone stimulated breast cancer growth when used on its own (not used with finasteride).

 

[haidut]

It seems like the story is, from what I gathered from the references he cited, is that 5a-DHP activates MAPK, while progesterone inhibits it. This leads to tumors even in progesterone and estrogen receptor negative cell lines. The researchers tested multiple cell lines, also.

Yep, that is one mechanism. But in vivo, we need to look at the whole picture and all of the metabolites. So, the studies show that progesterone raises 5a-DHP and allopregnanolone levels in humans, and progesterone given on its own promoted breast cancer growth in that in vivo model. So, does that mean progesterone has to be "tamed" with a 5-AR blocker to be safe for breast cancer? Or does progesterone somehow always negate the possible negative effects of its metabolites?
Somebody else raised the same point about DHT. It is away from the parent (pregnenolone) and it is fully reduced steroid. But it does seem to be very beneficial in small doses.
Anyways, hopefully when the dust settles he will get a chance to respond.

 

[raypeatclips]

@haidut I am not expecting a reply from him, he didn't really seem particularly interested in the topic. Of course I will post it if I get one. If someone else wants to ask him the progesterone question that would be good and if you are asking lots of questions please send him some money.

 

[haidut]

@haidut I am not expecting a reply from him, he didn't really seem particularly interested in the topic. Of course I will post it if I get one. If someone else wants to ask him the progesterone question that would be good and if you are asking lots of questions please send him some money.

Yeah, that's what I thought. I am sure he gets a ton of emails and there is only so much time he can spend on any one topic. I do appreciate his feedback though. How do people send him money - check, money order, etc?

 

[raypeatclips]

@haidut Yeah I've noticed he usually replies to an initial email question I ask him, and only replies to the follow ups if its an interesting question. Check your PM's.

 

[Pointless]

Yep, that is one mechanism. But in vivo, we need to look at the whole picture and all of the metabolites. So, the studies show that progesterone raises 5a-DHP and allopregnanolone levels in humans, and progesterone given on its own promoted breast cancer growth in that in vivo model. So, does that mean progesterone has to be "tamed" with a 5-AR blocker to be safe for breast cancer? Or does progesterone somehow always negate the possible negative effects of its metabolites?
Somebody else raised the same point about DHT. It is away from the parent (pregnenolone) and it is fully reduced steroid. But it does seem to be very beneficial in small doses.
Anyways, hopefully when the dust settles he will get a chance to respond.

Either way the cancer connection is troubling, to be supplementing the metabolite that increases cell proliferation. I think the studies he cited make his stance clear.

 

[Koveras]

No problem, it's probably OK that way too. If he does responds or you get a chance to ask him later, I would be very interested to hear his thoughts on the progesterone to breast cancer connection. Giving progesterone to humans raises 5a-DHP and allopregnanolone as shown by the human studies. Does that mean progesterone may be inappropriate in the context of breast cancer unless administered (God forbid) with a 5-AR inhibitor? That study clearly showed that progesterone stimulated breast cancer growth when used on its own (not used with finasteride).

@haidut I am not expecting a reply from him, he didn't really seem particularly interested in the topic. Of course I will post it if I get one. If someone else wants to ask him the progesterone question that would be good and if you are asking lots of questions please send him some money.

Either way the cancer connection is troubling, to be supplementing the metabolite that increases cell proliferation. I think the studies he cited make his stance clear.

I think the answer lies herein: Another metabolite of progesterone, 3alpha-dihydroprogesterone, has opposing actions. Therefore 'whole' progesterone has more balanced effect on the cell.

J Steroid Biochem Mol Biol. 2010 Jan;118(1-2):125-32. doi: 10.1016/j.jsbmb.2009.11.005. Epub 2009 Nov 17.
Opposing actions of the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines.
Wiebe JP1, Beausoleil M, Zhang G, Cialacu V.

Previous studies have shown that breast tissues and breast cell lines convert progesterone (P) to 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) and that 3alphaHP suppresses, whereas 5alphaP promotes, cell proliferation and detachment. The objectives of the current studies were to determine if the 5alphaP- and 3alphaHP-induced changes in cell numbers are due to altered rates of mitosis and/or apoptosis, and if 3alphaHP and 5alphaP act on tumorigenic and non-tumorigenic cells, regardless of estrogen (E) and P receptor status. 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. The findings further support the hypothesis that progesterone metabolites are key regulatory hormones and that changes in their relative concentrations in the breast microenvironment determine whether breast tissues remain normal or become cancerous.

Breast Cancer Res. 2013 May 11;15(3):R38. doi: 10.1186/bcr3422.
Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors.
Wiebe JP1, Zhang G2,3, Welch I4, Cadieux-Pitre HA5.

INTRODUCTION:
Of the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.
METHODS:
ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS:
Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS:
The studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

 

[Koveras]

The combination of DHEA and 5a-DHP would probably be killer for breast growth(s)

In all seriousness though I think there is potential/utility for this product. Much caution is warranted though

 

[goodandevil]

I wonder if 5-alpha is is involved in supressing the pituitary response to stress, a switch to turn off emergency modes. I presume these cell lines were isolated from pituitary hormones but there does seem to be a different response from the pituitary vs other cells. It would make sense- progesterone comes back up, emergency response is terminated, pituitary becomes less sensitive to estrogen. Pure conjecture but perhaps 5adhp governs pituitary or hypothalamic sensitivity and the release of trophic hormones in emergency mode.

 

[haidut]

I think the answer lies herein: Another metabolite of progesterone, 3alpha-dihydroprogesterone, has opposing actions. Therefore 'whole' progesterone has more balanced effect on the cell.

J Steroid Biochem Mol Biol. 2010 Jan;118(1-2):125-32. doi: 10.1016/j.jsbmb.2009.11.005. Epub 2009 Nov 17.
Opposing actions of the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines.
Wiebe JP1, Beausoleil M, Zhang G, Cialacu V.

Previous studies have shown that breast tissues and breast cell lines convert progesterone (P) to 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) and that 3alphaHP suppresses, whereas 5alphaP promotes, cell proliferation and detachment. The objectives of the current studies were to determine if the 5alphaP- and 3alphaHP-induced changes in cell numbers are due to altered rates of mitosis and/or apoptosis, and if 3alphaHP and 5alphaP act on tumorigenic and non-tumorigenic cells, regardless of estrogen (E) and P receptor status. 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. The findings further support the hypothesis that progesterone metabolites are key regulatory hormones and that changes in their relative concentrations in the breast microenvironment determine whether breast tissues remain normal or become cancerous.

Breast Cancer Res. 2013 May 11;15(3):R38. doi: 10.1186/bcr3422.
Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors.
Wiebe JP1, Zhang G2,3, Welch I4, Cadieux-Pitre HA5.

INTRODUCTION:
Of the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.
METHODS:
ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.
RESULTS:
Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.
CONCLUSIONS:
The studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

The problem is that progesterone converts down the 5-AR pathway and that is why it is given as a pro-drug for allopregnanolone in humans. That study I posted from the same authors clearly shows that progesterone itself can stimulate breast cancer growth UNLESS administered with finasteride. So, even if the theory is that progesterone itself can balance the negative effects 5a-DHP then why did regular progesterone still simulate breast cancer growth when not administered with finasteride?

 

[haidut]

I wonder if 5-alpha is is involved in supressing the pituitary response to stress, a switch to turn off emergency modes. I presume these cell lines were isolated from pituitary hormones but there does seem to be a different response from the pituitary vs other cells. It would make sense- progesterone comes back up, emergency response is terminated, pituitary becomes less sensitive to estrogen. Pure conjecture but perhaps 5adhp governs pituitary or hypothalamic sensitivity and the release of trophic hormones in emergency mode.

Yes, it does. 5-AR is involved in breaking down cortisol and I maybe even ACTH. Suprpessing 5-AR with finasteride augments the stress response (ACTH and cortisol release) as I posted in another thread. So, what do you think those trophic hormones that would have been released (unless 5a-DHP was administered) would be? There are some studies showing increased prolactin stimulated DHEA synthesis, but if you have other ones in mind please share.

 

[haidut]

Either way the cancer connection is troubling, to be supplementing the metabolite that increases cell proliferation. I think the studies he cited make his stance clear.

Yep, that's what I thought as well. I will wait for the dust to settle a bit and then email him about the whole progesterone cascade. There are in vivo studies with pregnenolone as well showing it promoted cancer growth strongly (prostate). The dose used was high, but still, not something you'd expect from an upstream steroid that is expected to be safe in any dose.

 

[Koveras]

The problem is that progesterone converts down the 5-AR pathway and that is why it is given as a pro-drug for allopregnanolone in humans. That study I posted from the same authors clearly shows that progesterone itself can stimulate breast cancer growth UNLESS administered with finasteride. So, even if the theory is that progesterone itself can balance the negative effects 5a-DHP then why did regular progesterone still simulate breast cancer growth when not administered with finasteride?

From the study:

"Hormone measurements showed significantly higher levels of 5αP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5αP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. "

Some mice had no issues with progesterone.

My guess - the difference is prolactin. Prolactin induces 5a-reductase activity (along with aromatase) and this is one of, if not the main, mechanism that it makes tissues such as the prostate, breast, and hair more sensitive to the effects of hormones. Unfortunately not measured in this study.

 

[Makrosky]

Yep, that's what I thought as well. I will wait for the dust to settle a bit and then email him about the whole progesterone cascade. There are in vivo studies with pregnenolone as well showing it promoted cancer growth strongly (prostate). The dose used was high, but still, not something you'd expect from an upstream steroid that is expected to be safe in any dose.

Whaaaat??? Plain pregnenolone promoting cancer growth strongly?? Could you please share that study??


[ moderator edit: replies moved to Pregnenolone And Prostate Cancer ]

 

[goodandevil]

From the study:

"Hormone measurements showed significantly higher levels of 5αP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5αP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. "

Some mice had no issues with progesterone.

My guess - the difference is prolactin. Prolactin induces 5a-reductase activity (along with aromatase) and this is one of, if not the main, mechanism that it makes tissues such as the prostate, breast, and hair more sensitive to the effects of hormones. Unfortunately not measured in this study.

@Koveras
Very interesting factoid with regards to hair loss and 5 alpha reductase. James like.

 

[Koveras]

Very interesting factoid with regards to hair loss and 5 alpha reductase. James like.

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…"

 

[goodandevil]

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.

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.

Prolactin effect on the permeability of human benign hyperplastic prostate to testosterone

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.

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.

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.

. 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.

Effects of testosterone and prolactin on rat prostatic weight, 5alpha-reductase, and arginase. - PubMed - NCBI
. It was shown that ovine prolactin may have an enhancing effect on the prostatic weight, 5alpha-reductase, 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…"

@Koveras Fascinating. If it is true that increased pituitary hormones represent an "emergency mode", then it seems intuitively obvious, according to your studies, that increased 5 alpha reductase levels are also associated with this emergency mode. This might also explain the association of 5 alpha dihydroprogesterone with cancer. Moreover, the association of prolactin with 5 alpha reductase would seem to explain prolactin as a confounding factor in elucidating the "goodness" of DHT. excellent and very interesting studies.

I don't know, but I'm guessing @haidut that more than ACTH is secreted from the pituitary under a stress response, or perhaps we must broaden our definition of the stress response to include at the least all of the anterior pituitary hormones. makes sense what ray said, about hypophysectomized animals, with good thyroid function, living longer. But without adequate thyroid function maybe shutting down the pituitary is not so good.

 

[Koveras]

@Koveras Fascinating. If it is true that increased pituitary hormones represent an "emergency mode", then it seems intuitively obvious, according to your studies, that increased 5 alpha reductase levels are also associated with this emergency mode. This might also explain the association of 5 alpha dihydroprogesterone with cancer. Moreover, the association of prolactin with 5 alpha reductase would seem to explain prolactin as a confounding factor in elucidating the "goodness" of DHT. excellent and very interesting studies.

I don't know, but I'm guessing @haidut that more than ACTH is secreted from the pituitary under a stress response, or perhaps we must broaden our definition of the stress response to include at the least all of the anterior pituitary hormones. makes sense what ray said, about hypophysectomized animals, with good thyroid function, living longer. But without adequate thyroid function maybe shutting down the pituitary is not so good.

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.”