Upregulate Enzymes for Higher Testosterone?

In the body, specifically the leydig cells in the testes, 17beta-HSD3 is the enzyme responsible for conversion of androstenedione to testosterone. In the heyday of prohormones back in the early 2000’s, I always wondered if there was a way to upregulate this enzyme to help with the conversion of either natural or exogenous androstenedione.

Same thing with 4-androstenediol which uses the 3beta-hydroxysteroid dehydrogenase (3beta-HSD)enzyme…how does one upregulate this?

Green tea and dark chocolate apparently contain high amounts of epicatechin that upregulates 17beta-HSD3, but I have not found any information or anecdotal evidence that intake of these substances significantly affected testosterone levels.

Anyone do any research in this area?

Similar question: any possible NEGATIVE effects from upregulation?

[quote]buffd_samurai wrote:
In the body, specifically the leydig cells in the testes, 17beta-HSD3 is the enzyme responsible for conversion of androstenedione to testosterone. In the heyday of prohormones back in the early 2000’s, I always wondered if there was a way to upregulate this enzyme to help with the conversion of either natural or exogenous androstenedione.

Same thing with 4-androstenediol which uses the 3beta-hydroxysteroid dehydrogenase (3beta-HSD)enzyme…how does one upregulate this?

Green tea and dark chocolate apparently contain high amounts of epicatechin that upregulates 17beta-HSD3, but I have not found any information or anecdotal evidence that intake of these substances significantly affected testosterone levels.

Anyone do any research in this area?[/quote]

Probably not what you are looking for:

[i]
Mol Med. 2011;17(7-8):657-64. doi: 10.2119/molmed.2010.00143. Epub 2011 Feb 22.
Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer.
Pfeiffer MJ1, Smit FP, Sedelaar JP, Schalken JA

Abstract
Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent tumors. To study this hypothesis, we assessed the expression of several steroidogenic enzymes and stem cell markers in clinical PCa samples and cell cultures during androgen depletion. Gene expression profiles were determined by microarray or qRT-PCR. In addition, we measured cell viability and analyzed stem cell marker expression in DuCaP cells by immunocytochemistry. Seventy patient samples from different stages of PCa, and the PCa cell line DuCaP were included in this study. The androgen receptor (AR) and enzymes (AKR1C3, HSD17B2, HSD17B3, UGT2B15 and UGT2B17 ) that are involved in the metabolism of adrenal steroids were upregulated in castration resistant prostate cancer (CRPC). In vitro, some DuCaP cells survived androgen depletion, and eventually gave rise to a culture adapted to these conditions. During and after this transition, most of the steroidogenic enzymes were upregulated. These cells also are enriched with stem/progenitor cell markers cytokeratin 5 (CK5) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, putative stem/progenitor cell markers CK5, c-Kit, nestin, CD44, c-met, ALDH1A1, α2-integrin, CD133, ABCG2, CXCR4 and POU5F1 were upregulated in clinical CRPC. The upregulation of steroidogenic enzymes and stem cell markers in recurrent tumors suggests that cancer initiating cells can expand by adaptation to their T/DHT deprived environment. Therapies targeting the metabolism of adrenal steroids by the tumor may prove effective in preventing tumor regrowth.[/i]

But here is something useful:

[i]DNA Cell Biol. 2011 Sep;30(9):661-9. doi: 10.1089/dna.2010.1192. Epub 2011 May 12.
Butyrate induces expression of 17β-hydroxysteroid dehydrogenase type 1 in HT29 and SW707 colorectal cancer cells.
RawÅ?uszko AA1, Krokowicz P, JagodziÅ?ski PP.
Author information

Abstract
Epidemiological studies have revealed that butyrate and 17β-estradiol (E2) may decrease the incidence of colorectal cancer (CRC). In peripheral tissue, E2 can be produced locally by 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) estrone (E1) reduction. Using quantitative real-time polymerase chain reaction and western blotting analysis, we found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in HT29 and SW707 CRC cells. Chromatin immunoprecipitation analysis showed that upregulation of these transcript levels correlated with an increase in binding of Polymerase II to proximal and distal promoters of HSD17B1. Moreover, we observed that upregulation of HSD17B1 protein levels was associated with increased conversion of E1 to E2 in HT29 and SW707 CRC cells. Since sodium butyrate increases the conversion of E1 to E2, our findings may support the validity of butyrate in the prophylaxis of CRC incidence.[/i]

Note that something as simple as sodium butyrate in vitro increases HSD17B1.
BUT…that you can’t eat butyrate and get that effect, and
the enzyme acts to increase the production of estrone to estradiol.

There ain’t no free lunch.

DrSkeptix, thanks for the references and the abstracts…but to be quite frank, I’m a bit dense when it comes to deciphering the jargon indicated in the references, and also, I am not sure the references really point to what I’m getting at.

1st of all (again, keep in mind I said I was dense), the cancer related stuff doesn’t indicate increasing the enzymes will CAUSE the cancer, but if you have the cancers already the enzymes could cause problems. This is something that almost can be said for so many things.

The enzyme I am specifically interested in is 17beta-HSD type 3, not type 1. Type 3 is the enzyme in the leydig cells…type 1 from what I’ve read indeed increases estrogen, something we don’t want as you have indicated. The second reference says nothing about type 3 though.

Works I guess, but doubt it’s a big deal.

Steroids. 2012 May;77(6):691-5
Dietary green and white teas suppress UDP-glucuronosyltransferase UGT2B17 mediated testosterone glucuronidation.
Jenkinson C., Petroczi A, Barker J, Naughton

The anabolic steroid testosterone can be used by athletes to enhance athletic performance and muscle growth. UDP-glucuronosyltransferase (UGT2B17) is the key enzyme involved in the glucuronidation of testosterone to testosterone glucuronide, which also serves as a marker for the testosterone/epitestosterone (T/E) ratio used to detect testosterone abuse in sport. Inhibitors of testosterone glucuronidation could have an impact on circulating testosterone levels, thus aiding performance, as well as potentially affecting the urinary T/E ratio and therefore masking testosterone abuse. Previous reports have revealed that non-steroidal, anti-inflammatory drugs, diclofenac and ibuprofen, inhibit the UGT2B17 enzyme. The aim of this study is to analyse dietary tea samples for inhibition of testosterone glucuronidation and, where inhibition is present, to identify the active compounds. Analysis of testosterone glucuronidation was conducted by performing UGT2B17 assays with detection of un-glucuronidated testosterone using high performance liquid chromatography. The results from this study showed that testosterone glucuronidation was inhibited by the green and white tea extracts, along with specific catechin compounds, notably: epicatechin, epigallocatechin gallate (EGCG) and catechin gallate. The IC50 inhibition value for EGCG was determined, using a Dixon plot, to be 64 μM, equalling the most active NSAID inhibitor diclofenac. Thus, common foodstuffs and their constituents, for the first time, have been identified as inhibitors of a key enzyme involved in testosterone glucuronidation. Whilst these common compounds are not substrates of the UGT2B17 enzyme, we showed that they inhibit testosterone glucuronidation which may have implications on current doping control in sport.

Butyrate, of course, can be delivered by intestinal bacteria primarily as they break down certain fibers, Oligosaccharides in particular I think. The other pretty much proven way to boost low T is 250 mg of zinc a day.

[quote]buffd_samurai wrote:
DrSkeptix, thanks for the references and the abstracts…but to be quite frank, I’m a bit dense when it comes to deciphering the jargon indicated in the references, and also, I am not sure the references really point to what I’m getting at.

1st of all (again, keep in mind I said I was dense), the cancer related stuff doesn’t indicate increasing the enzymes will CAUSE the cancer, but if you have the cancers already the enzymes could cause problems. This is something that almost can be said for so many things.

The enzyme I am specifically interested in is 17beta-HSD type 3, not type 1. Type 3 is the enzyme in the leydig cells…type 1 from what I’ve read indeed increases estrogen, something we don’t want as you have indicated. The second reference says nothing about type 3 though.

[/quote]

Oh…of course!
There seems to be far more interest in induction and suppression of type 1, perhaps because the in vitro model is easier to manage (choriocarcinoma, placental cells, etc) than Leydig cells.

I owe you, Buff Sam: I learned something, too. We are told that the type 3 isoenzyme is isolated to the testis. Not so, apparently, since it is inducible in platelets. (Thereby suggesting a connection to JAK and to RXR retinoids. But we should not go there, either; RXR induces type 1). But this would mean that type 1 may not be isolated to Leydig cells–do castrate men produce T in fat and adrenal cells? Possibly. (There is also a rare disease of type 3 deficiency wherein genotypical males are phenotypically female.)

But, no, I could not find in vitro or in vivo studies of something that specifically induces type 3 17betaHSD.

DrSkeptix, the more minds that focus on a question, the better the experience and growth opportunity for expansion of knowledge. You too have taught me something; I appreciate that.

Something from Alpha Male writeup: “Eurycoma imparts its effects by selectively controlling the conversion of DHEA and other naturally occurring androgens into Testosterone. In fact, it even works when the testes are non-responsive to Luteinizing hormone. As long as the substrate hormones are present (and they’re present in everyone), Eurycoma works.”

The ONLY way this can be is if Eurycoma truly upregulates both 3beta-HSD and 17betaHSD-type3 and either down regulates aromatase or at least keep it in check somehow. From the biochemistry pathways, this is the only way I can fathom how this is happening. BUT, I need to see the research that led to that conclusion.

Biotest’s RED KAT product was their standalone Eurycoma product before they introduced it into Alpha Male. It also contained Scalaremax which was the precursor to Carbolin 19 (in terms of what function the ingredient was added in for…namely cAMP upregulation). Somehow that product worked much better for me than Alpha Male or even Carbolin 19 ever did for me. I don’t know if the other ingredients in Alpha Male somehow interferes with one another in my biochemistry or if Sclaremax increased cAMP better in me than Carbolin 19, but that is not a far fetched possibility. We are all different.

[quote]buffd_samurai wrote:
DrSkeptix, the more minds that focus on a question, the better the experience and growth opportunity for expansion of knowledge. You too have taught me something; I appreciate that.

Something from Alpha Male writeup: “Eurycoma imparts its effects by selectively controlling the conversion of DHEA and other naturally occurring androgens into Testosterone. In fact, it even works when the testes are non-responsive to Luteinizing hormone. As long as the substrate hormones are present (and they’re present in everyone), Eurycoma works.”

The ONLY way this can be is if Eurycoma truly upregulates both 3beta-HSD and 17betaHSD-type3 and either down regulates aromatase or at least keep it in check somehow. From the biochemistry pathways, this is the only way I can fathom how this is happening. BUT, I need to see the research that led to that conclusion.

Biotest’s RED KAT product was their standalone Eurycoma product before they introduced it into Alpha Male. It also contained Scalaremax which was the precursor to Carbolin 19 (in terms of what function the ingredient was added in for…namely cAMP upregulation). Somehow that product worked much better for me than Alpha Male or even Carbolin 19 ever did for me. I don’t know if the other ingredients in Alpha Male somehow interferes with one another in my biochemistry or if Sclaremax increased cAMP better in me than Carbolin 19, but that is not a far fetched possibility. We are all different.
[/quote]

You may find this interesting:

[i]J Ethnopharmacol. 2013 Aug 26;149(1):201-7. doi: 10.1016/j.jep.2013.06.023. Epub 2013 Jun 27.
Eurycomanone, the major quassinoid in Eurycoma longifolia root extract increases spermatogenesis by inhibiting the activity of phosphodiesterase and aromatase in steroidogenesis.
Low BS1, Choi SB, Abdul Wahab H, Das PK, Chan KL.
Author information

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Eurycoma longifolia Jack (Simaroubaceae family), known locally as ‘Tongkat Ali’ by the ethnic population, is popularly taken as a traditional remedy to improve the male libido, sexual prowess and fertility. Presently, many tea, coffee and carbonated beverages, pre-mixed with the root extract are available commercially for the improvement of general health and labido. Eurycomanone, the highest concentrated quassinoid in the root extract of E. longifolia improved fertility by increasing testosterone and spermatogenesis of rats through the hypothalamus-pituitary-gonadal axis, but the mechanisms underlying the effects are not totally clear.
AIM OF THE STUDY:
To provide evidences on the plant ethnopharmacological use and the involvement of eurycomanone, the major indigenous plant quassinoid in testosterone steroidogenesis and spermatogenesis increase.
MATERIAL AND METHODS:
The rat testicular Leydig cell-rich interstitial cells were isolated and incubated in the culture medium M199. The viability of the cells was determined with trypan blue staining and the concentration of the viable cells was counted with a haemocytometer. The 3β-hydroxysteroid dehydrogenase (HSD) staining method was used to measure the abundance of Leydig cells in the preparation. Eurycomanone and the standard steroidogenesis inhibitors were incubated with 1.0 � 10(5) cells, and after 2h, the testosterone and the oestrogen concentrations were determined by the ELISA method. Computational molecular docking was performed to determine the binding affinity of the compound at the respective steroidogenesis enzymes.
RESULTS:
Eurycomanone (EN) significantly increased testosterone production dose-dependently at 0.1, 1.0 and 10.0 μM (P<0.05), but the two lower doses when combined with 3-isobutyl-1-methylxanthine (IBMX), the phosphodiesterase inhibitor were not significantly higher than EN or IBMX alone, except at a higher concentration. The molecular docking studies indicated EN and IBMX were binding at different sites of the enzyme. EN has no reversal of inhibition by aminoglutethimide, ketoconazole or nifedipine at the respective steroidogenesis enzyme. The quassinoid was also non-responsive to the inhibition of oestrogen receptor by tamoxifen, but displayed improved formestane inhibition of aromatase in reducing oestrogen production. The molecular docking studies further supported that EN and formestane bound to aromatase with similar orientations and free energy binding values.
CONCLUSION:
Eurycomanone enhanced testosterone steroidogenesis at the Leydig cells by inhibiting aromatase conversion of testosterone to oestrogen, and at a high concentration may also involve phosphodiesterase inhibition. The quassinoid may be worthy for further development as a phytomedicine to treat testosterone-deficient idiopathic male infertility and sterility.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
[/i]

A note of warning: just because they found something, it does not mean they found everything. Finding one mechanism of action does not preclude others.

A nod to Carbolin 19: among the intermediaries in 17betaHSD activation is, no surprise, cyclic AMP. All the more credit to our mutual friend, Cy Willson, and to Carbolin 19.