New Study: Long Term Dutasteride Is Associated With Metabolic Alterations

[Feelsbadman.jpg]

Back to this study https://www.ncbi.nlm.nih.gov/pubmed/30971393 (shows Finasteride and Dutasteride BOTH are a risk factor for type 2 Diabetes).

This result is shocking because finasteride does not inhibit 5AR1 (obviously) to any appreciable degree. However, Finasteride apparently does inhibit another enzyme in the liver that also inactivates glucocorticoids, 5beta-reductase (AKR1D1).

Study showing that 5beta-reductase likely plays a role in NAFLD. https://www.endocrine-abstracts.org/ea/0056/ea0056oc6.1

Study showing 5beta-reductase is primarily active in the liver and a crucial regulator in steroid hormone clearance and inhibited by Finasteride but not Dutasteride. https://www.endocrine-abstracts.org/ea/0041/ea0041GP174

This study shows that 5AR is elevated and not 5BR in NAFLD and that the increase in 5AR is a "compensatory mechanism to decrease local glucocorticoid availability in an attempt to preserve hepatic metabolic phenotype." They believe the increased 5AR(both type 1 and 2) is not the cause but a result of NAFLD. https://www.endocrine-abstracts.org/ea/0019/ea0019oc18

So dutasteride inhibits 2 enzymes(5AR 1 and 2) related to glucocorticoid metabolism as does Finasteride (5AR 2 and 5BR). This might be why they have similar risk for type 2 diabetes (finasteride actually seemed to have higher risk, unless I'm reading the results wrong.)

However this to me still completely contradicts the fact that Testosterone administered with Dutasteride increases insulin sensitivity more than T alone or even T with an aromatase inhibitor. https://www.ncbi.nlm.nih.gov/pubmed/24344872

This shows that DHT actually worsens insulin sensitivity. It is not the lack of DHT that is increasing the risk for type 2 diabetes but rather the increased exposure to glucocorticoids due reduced clearance from 5AR inhibition. However, ample T seems to completely offset this and actually boost insulin sensitivity. The only thing I can think of is that T + Estradiol increase insulin sensitivity which means lower insulin. Glucocorticoids
in the absence of insulin actually burn fat. So the risk for type 2 diabetes would really only apply to those who have low testosterone. Guess who was studied in https://www.ncbi.nlm.nih.gov/pubmed/30971393 ? Men taking these drugs for prostate purposes which is most likely middle age or older, when T starts to decline.

I doubt younger men with ample T will have any problems with NAFLD or type 2 diabetes. If older, one could consider TRT since we know that T+dutasteride = better insulin sensitivity.

 

[Feelsbadman.jpg]

I don't see how exercising will ameliorate impaired gluccocorticoid clearance induced by 5ar1 inhibition.

This is an interesting comment but I believe exercise will still help by reducing glucocorticoid production.

https://www.ncbi.nlm.nih.gov/pubmed/22233384

This study shows a decrease in 11 β-HSD type 1 following weight loss. This enzyme converts cortisone to cortisol and by decreasing it, you decrease glucocorticoid exposure to receptors. Less Cortisol means less 5AR is needed to clear it out.

Also, exercise increases insulin sensitivity and lower insulin. Glucocorticoids actually promote fat loss in the absence of insulin further reducing the risk for type 2 Diabetes and NAFLD.

Furthermore, too much 5AR activity can cause excessive clearance of glucocorticoids which will in turn activate the HPA axis to stimulate more glucocorticoids. By inhibiting 5AR, you reduce the rate at which glucocorticoids are metabolized (there are other pathways besides just 5AR 1 and 2 that do this) which will in turn cause negative feedback to the HPA to reduce production.

I am speculating a lot with this but it seems reasonable that Dutasteride may actually preserve hypalthmic sensitivity to the negative feedback of cortisol due to decreased deactivation of glucocorticoids, it could prevent over stimulation of the HPA axis. The only real danger from elevated glucocorticoids in peripheral tissue such as the liver that I can see comes from high insulin which leads to fat accumulation though this probably an oversimplification but cortisol's effects are largely determined by the presence or absence of other hormones.

So high insulin diet with sedentary lifestyle, 5AR inhibition leads to fat gain faster than otherwise (but potentially protects against cancer like tumors in the liver). However, a low insulin stimulating diet with physical activity could cause 5AR inhibition to actually assist with fat loss.

 

[Michael1986]

Dutasteride may not be all bad news. Here are two studies which provide evidence that Dutasteride has neuro-protective properties in Parkinson's disease:

Study 1:
Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice:
http://www.sciencedirect.com/science/article/pii/S0960076017302698
Highlights:
1. Dutasteride prevented the MPTP-induced striatal loss of dopamine contents.
2. Dutasteride prevented striatal MPTP-induced loss of DAT and VMAT2 transporters.
3. Dutasteride increased striatal DAT binding and glycosylation.
4. Dutasteride affected androgen and progesterone metabolism in brain and plasma.
5. Dutasteride prevented MPTP-induced increase of GFAP.

Study 2:
The 5α-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson's disease: http://www.sciencedirect.com/science/article/pii/S0028390815001963
Highlights:
• The 5α-reductase inhibitors Dutasteride and Finasteride were studied in MPTP mice.
• Dutasteride prevented the MPTP-induced striatal loss of dopamine concentrations.
• Dutasteride prevented striatal MPTP-induced loss of DAT and VMAT2 transporters.
• Finasteride did not protect striatal dopamine concentrations, DAT or VMAT2 levels.
• Dutasteride and Finasteride prevented MPTP-induced decreases of plasma testosterone.
And the last paragraph reads:
In summary, our results showed that a 5α-reductase inhibitor, Dutasteride has neuroprotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers.

 

[Kaus Klinski]

Hi,

very interesting topic.

I'm currently on 0,5 mg Dutasreride e3d, so I assume that the amount of 5-AR-1 inhbition from that dose is negligible?

I'm not that keen on splitting finasteride pills, so I've chosen to just use Dutasteride 0,5 in the above manner (after taking a "full", i.e., 0,5 daily dose for several years with no side effects) to still have the benefits of a stronger and more stable type-2-inhibition (longer half life, higher affinity to bind to the specific enzyme than finasteride) while keeping the risks of 5-AR-1 inhibition to a minimum.

Do you more experienced guys think there is really something to the whole "diabetes being caused by 5-ARI" thing? Causation vs. correlation?

However, I reduced my dutasteride dose just to be sure (better safe then sorry). I don't see any difference in effectiveness for my hair on over a year on the reduced dose now.

The main reason I take oral dutasteride (I also recently started topical dutasteride once a day) is to offer some protection to my prostate, since Im on high dose TRT. I also take a small dose of anastrozole.

As for my hair, I'm a (very diffuse) Norwood 2a-3a and all I want is to prevent even further thinning/recession (looks stupid enough to have no hair line ;->).

regards
Kaus Klinski

 

[Manochoice]

Hi,

very interesting topic.

I'm currently on 0,5 mg Dutasreride e3d, so I assume that the amount of 5-AR-1 inhbition from that dose is negligible?

I'm not that keen on splitting finasteride pills, so I've chosen to just use Dutasteride 0,5 in the above manner (after taking a "full", i.e., 0,5 daily dose for several years with no side effects) to still have the benefits of a stronger and more stable type-2-inhibition (longer half life, higher affinity to bind to the specific enzyme than finasteride) while keeping the risks of 5-AR-1 inhibition to a minimum.

Do you more experienced guys think there is really something to the whole "diabetes being caused by 5-ARI" thing? Causation vs. correlation?

However, I reduced my dutasteride dose just to be sure (better safe then sorry). I don't see any difference in effectiveness for my hair on over a year on the reduced dose now.

The main reason I take oral dutasteride (I also recently started topical dutasteride once a day) is to offer some protection to my prostate, since Im on high dose TRT. I also take a small dose of anastrozole.

As for my hair, I'm a (very diffuse) Norwood 2a-3a and all I want is to prevent even further thinning/recession (looks stupid enough to have no hair line ;->).

regards
Kaus Klinski

https://www.sciencedaily.com/releases/2017/06/170622110452.htm

 

[Kaus Klinski]

@Manochoice:

Thanks for the link, I already stumbled across that information when doing my little research on the subject. But i'm not sure if you can directly compare older men treated for BPH with younger men treated for male pattern baldness, perhaps with a lower dose than the approved .5 mg

What gives me at least a little peace of mind is the fact, that dutasteride ("Zagallo") is officially approved for hair loss in japan/south korea.

Furthermore, we still have the pseudo hermaphrodites as a biological model for 5-AR-2 inhibition. AFAIK they don't have a higher risk for developing diabetes etc. than the rest of the population (I'm not sure though).

After all, it's probably like "choose your poison" (as so often in life).

regards
Kaus Klinski

 

[Michael1986]

The pseudohermaphrodites cannot be directly compared to finasteride or dutasteride users though, because the pseudohermaphrodites have normal levels of both 5ar type 1 and type 3.
As well as inhibiting 5ar type 2, finasteride and dutasteride both potently inhibit 5ar type 3, and dutasteride also partially inhibits 5ar type 1. The type 3 enzyme plays a critical role in cell metabolism and glycosylation.

 

[Kaus Klinski]

Hi,

I'm aware of the partial inhibition of the type 1 enzyme by dutasteride (and the fact that the pseudos have both fully working 5-ar1 and 3 enzymes), but shouldn't a daily dose of ~0.1 mg leave most of the 5-ar1 untouched? As for the 5-ar3, I thought it would only be inhibited by finasteride, but not dutasteride. Somebody once mentioned that on this forum (I think) and said it was a myth that dutasteride inhibits (much of) 5-ar3. Then again, it's probably also dose dependent.

reagrds

 

[Michael1986]

Hi,

I'm aware of the partial inhibition of the type 1 enzyme by dutasteride (and the fact that the pseudos have both fully working 5-ar1 and 3 enzymes), but shouldn't a daily dose of ~0.1 mg leave most of the 5-ar1 untouched? As for the 5-ar3, I thought it would only be inhibited by finasteride, but not dutasteride. Somebody once mentioned that on this forum (I think) and said it was a myth that dutasteride inhibits (much of) 5-ar3. Then again, it's probably also dose dependent.

reagrds

If you are taking 0.5mg of dutasteride every third day, that is correct that only a very small amount of 5ar type 1 will be inhibited. I saw a graph once which showed 5ar type 1 and type 2 inhibition rates from different doses of dutasteride. If I recall correctly, the graph showed that less than 15% of 5ar type 1 will be inhibited by taking 0.5mg of dutasteride every third day.
Dutasteride and finasteride both potently inhibit 5ar type 3, according to the following study: https://www.ncbi.nlm.nih.gov/pubmed/25961201

 

[Kaus Klinski]

Hi,

hmmm, but are you sure the type 3 enzyme is linked to reduced insulin sensitivity? I only found some evidence for the type 1 enzyme, like this:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207930/

regards
Kaus Klinski

 

[Michael1986]

Hi,

hmmm, but are you sure the type 3 enzyme is linked to reduced insulin sensitivity? I only found some evidence for the type 1 enzyme, like this:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207930/

regards
Kaus Klinski

I did a google search and wasn't able to find any evidence of a role that the type 3 enzyme plays in insulin sensitivity / diabetes. All I know is that it plays a crucial role in cell metabolism and glycosylation, and there is also evidence that it converts testosterone to DHT, and so it could be involved in hair loss.
Despite that 5ar type 3 could possibly play a role in hair loss, it would appear that it is not a good thing that this enzyme is potently inhibited by finasteride and dutasteride. I actually found a second study that backs up the findings of the study I quoted above; dutasteride potently inhibits 5ar type 3: https://www.researchgate.net/public..._OF_5-ALPHA_REDUCTASE_3_IN_STEROID_METABOLISM

 

[Kaus Klinski]

I'm curious about the amount of 5-ar3 that is actually inhibited by lower doses of finasteride or dutasteride, i.e. the standard dose of finasteride for male pattern baldness (1 mg). It might be possible (but that's just pure layman's speculation) that a low dose of dutasteride *may* have less of a potential to inhibit 5-ar3 than the standard dose of finasteride (given the in vitro ic50 values) in vivo. But who knows. Hopefully, with the dose I'm currently taking, not too much of 5-ar3 is inhibited.

Regards
Kaus Klinski

 

[Feelsbadman.jpg]

Hi,

very interesting topic.

I'm currently on 0,5 mg Dutasreride e3d, so I assume that the amount of 5-AR-1 inhbition from that dose is negligible?

I'm not that keen on splitting finasteride pills, so I've chosen to just use Dutasteride 0,5 in the above manner (after taking a "full", i.e., 0,5 daily dose for several years with no side effects) to still have the benefits of a stronger and more stable type-2-inhibition (longer half life, higher affinity to bind to the specific enzyme than finasteride) while keeping the risks of 5-AR-1 inhibition to a minimum.

Do you more experienced guys think there is really something to the whole "diabetes being caused by 5-ARI" thing? Causation vs. correlation?

However, I reduced my dutasteride dose just to be sure (better safe then sorry). I don't see any difference in effectiveness for my hair on over a year on the reduced dose now.

The main reason I take oral dutasteride (I also recently started topical dutasteride once a day) is to offer some protection to my prostate, since Im on high dose TRT. I also take a small dose of anastrozole.

As for my hair, I'm a (very diffuse) Norwood 2a-3a and all I want is to prevent even further thinning/recession (looks stupid enough to have no hair line ;->).

regards
Kaus Klinski

I just made several posts addressing this question if you read through the thread.

 

[Feelsbadman.jpg]

The pseudohermaphrodites cannot be directly compared to finasteride or dutasteride users though, because the pseudohermaphrodites have normal levels of both 5ar type 1 and type 3.
As well as inhibiting 5ar type 2, finasteride and dutasteride both potently inhibit 5ar type 3, and dutasteride also partially inhibits 5ar type 1. The type 3 enzyme plays a critical role in cell metabolism and glycosylation.

5AR type 3 was not shown to be in the liver or involved in glucocorticoid metabolism in any way whatsoever in the studies that are studying finasteride and dutasteride and metabolic alterations. Type 3 5AR seems to be mostly involved in cancer from what I have briefly looked at.

Finasteride has been shown to have a comparable risk as dutasteride for type 2 diabetes which I also addressed just a few posts up.

 

[Kaus Klinski]

@Feelsbadman.jpg:

Alright, will reread your posts later that day, heading to the gym now ;-)

regards
Kaus Klinski

 

[Feelsbadman.jpg]

My own speculation.

DHT is a carcinogenic hormone. So if increased 5AR expression is a coping mechanism to clear out excessive glucocorticoids to minimize their interaction with insulin (this seems to be the prevailing theory based off of"Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man" by Tomlinson et al.) increased DHT could be an unintended consequence. Excessive and prolonged DHT exposure in the liver could lead to cancer. However, it seems odd that such a mechanism would prioritize limiting hepatic steatosis at the expense of possible (actually probable in this study) cancer tumors. Perhaps the modern diet has simply not been around enough for natural selection to sort this out?

Looks like this speculation may be correct.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110552/

https://www.ncbi.nlm.nih.gov/pubmed/17369855

Dutasteride could actually prevent liver cancer.

 

[Kaus Klinski]

@Feelsbadman.jpg:

So, you'd say that low dose dutasteride (~ 0.1 mg) is actually the better/safer choice than finasteride, because at the low dose it doesn't inhibit much 5-ar1 (but about as much 5-ar2 as 5 mg of finasteride would do), doesn't inhibit intrahepatic 5-br at all and in addition, inhibits a significant amount of 5-ar3 (as finasteride does as well), but that doesn't contribute to a higher risk of developing NAFLD or Diabetes, correct?

regards
Kaus Klinski

 

[Kaus Klinski]

5AR type 3 was not shown to be in the liver or involved in glucocorticoid metabolism in any way whatsoever

According to the document I attached, 5-ar3 actually *is* expressed in liver tissue, even more so than the other 5-ar enzymes (see the graph on page 4 of the .pdf)

 

[Feelsbadman.jpg]

@Feelsbadman.jpg:

So, you'd say that low dose dutasteride (~ 0.1 mg) is actually the better/safer choice than finasteride, because at the low dose it doesn't inhibit much 5-ar1 (but about as much 5-ar2 as 5 mg of finasteride would do), doesn't inhibit intrahepatic 5-br at all and in addition, inhibits a significant amount of 5-ar3 (as finasteride does as well), but that doesn't contribute to a higher risk of developing NAFLD or Diabetes, correct?

regards
Kaus Klinski

I am saying that it is ridiculous to worry about these side effects with dutasteride but not finasteride when they both carry the same risk, at least for type 2 diabetes. The research shows that 5AR1 inhibition leads to faster progression of NAFLD (on a western style diet /w sedentarism) but prevents the very difficult to treat liver cancer (what NAFLD leads to).

5beta-reductase has not been researched much for it's involvement in NAFLD but based on the studies I posted it seems likely that it is significant. We don't know if finasteride could actually end up being worse off than dutasteride in that regard.

 

[Feelsbadman.jpg]

5AR type 3 was not shown to be in the liver or involved in glucocorticoid metabolism in any way whatsoever in the studies that are studying finasteride and dutasteride and metabolic alterations.

According to the document I attached, 5-ar3 actually *is* expressed in liver tissue, even more so than the other 5-ar enzymes (see the graph on page 4 of the .pdf)

That study is interesting and it does indeed show that there is 5AR3 in the liver. However, it does not investigate the role of 5AR3 in the liver. It is likely that it performs a similar role in glucocorticoid metabolism. Unfortunately, in the studies looking at 5AR and glucocorticoid metabolism and their role in NAFLD and insulin resistance, type 3 is not mentioned, at least from what I can see from my research. From my email correspondence with with one of the study authors (a PhD in metabolic endocrinology), there are a lot unknowns and research is still ongoing in this area.

It is a bit of a moot point however when comparing the safety of finasteride vs dutasteride since they both inhibit 5AR type 3. Basically, if you are worried about the metabolic effects of dutasteride to the point you won't take it, you probably shouldn't take finasteride either.