Part 3 Of 4: Attacking DHT By Decreasing Androgen Receptors

Rob Guides, Misc. Research 14 Comments

Read time: 10 minutes

Note: this is part three of a four-part series — a master guide to reducing DHT levels for hair loss. Missed the earlier articles? Read part one here, and part two here.

Summary So Far: Decrease DHT With Free Testosterone, 5-Alpha Reductase

In the first article, we uncovered what DHT is, how it’s made, the DHT-hair loss connection, and how we can reduce DHT (and maybe fight hair loss) by using four major levers.

  1. Decrease free testosterone
  2. Inhibit 5-alpha reductase
  3. Decrease androgen receptors
  4. …and one more we’ll reveal in the next article

Then we dove into all the mechanisms by which we can decrease DHT by using the first and second lever: reducing free testosterone and inhibiting 5-alpha reductase.

By the end of the second article, we summarized the mechanisms (but not all the drugs, foods, supplements, and treatments) targeting those first two levers:

But we still have two DHT-fighting levers left!

  1. Decreasing androgen receptors, and…
  2. A mystery lever (for the next and final article…)

This article is the third installment to our DHT-reducing mechanism series. We’ll uncover the third major DHT-reducing pathway – and its known mechanisms – in hopes of reducing DHT to slow, stop, or reverse pattern hair loss.

It all builds into our Master Flowchart: A Guide To All Major DHT Reducing Mechanisms To Fight Against Hair Loss.

What we’re covering now: decreasing DHT by reducing androgen receptors. And the research here is pretty exciting (at least to me).

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Reduce DHT By Decreasing Androgen Receptors

What Are Androgen Receptors?

Androgen receptors are the places inside a cell where androgens (testosterone, DHT, etc.) attach themselves. After an androgen attaches to an androgen receptor, these androgens can then influence a cell’s function.

Remember: DHT forms when free testosterone interacts with the enzyme type II 5-alpha reductase and converts that free testosterone into DHT. Then that DHT binds to a cell’s androgen receptor, where it influences that cell (and tissue). In the case of pattern hair loss, the kind of DHT people want to reduce is scalp tissue DHT.

Think of androgen receptors like a landing pad for DHT. Without an androgen receptor, DHT can’t attach to the cell and influence its function. And in the case of pattern hair loss – without androgen receptors, DHT can’t attach to scalp tissue DHT (the kind of DHT associates with hair thinning).

How Can We Decrease Androgen Receptors?

There are three main ways to decrease androgen receptors…

  1. Decrease total androgen production
  2. Decrease androgen receptor expression
  3. Block androgen receptors

Let’s dive into all three.

#1: Decreasing Total Androgen Production

We’ve actually covered this method before – albeit for reducing DHT via free testosterone. And to reiterate: this is a bad idea.

For instance, one way of blocking our body’s ability to produce androgens (and thereby reducing androgen receptor expression) is castration. Another way is to take drugs that change the brain signaling pathways in our hypothalamus so that our bodies convince themselves they need to produce less testosterone to thrive.

Yes, blocking total androgen production significantly decreases androgen receptor activity (likely because there are fewer total androgens available). But doing so comes attaches to serious side effects. And the costs of these side effects far outweigh any benefit to DHT reduction and hair health.

The consequences of this kind of DHT-reducing approach? Low/no libido, depression, sexual dysfunction, the list goes on. So when it comes to safely decreasing androgen receptors, please consider all other options aside from reducing total testosterone production.

In any case, here’s what this looks like in a flowchart:

Fortunately, there are other ways to target DHT by reducing androgen receptors. For instance: decreasing androgen receptor expression.

And this is where it gets interesting.

#2: Decreasing Androgen Receptor Expression

When we talk about decreasing androgen receptor expression, we’re not talking about manipulating androgen receptor activity by taking away the thing that tells our bodies to activate them – the androgens themselves. That’s the first mechanism – decreasing total androgen production.

This mechanism – decreasing androgen receptor expression – is about changing the actual environment of our tissues – so that fewer androgen receptors activate in those tissues.

I personally like this approach better. Why? Because rather than chemically (via drugs) or physically (via castration) reduce our androgen production to reduce androgen receptors, we’re instead changing the environment of a tissue where there are androgen receptors – so that fewer androgen receptors express.

And based on the evidence, this method is much safer.

One potential way to decrease androgen receptor expression?

Increase tissue oxygen levels.

Hypoxia (Oxygen Restriction) Increases Androgen Receptor Activity

In the prostate, reduced oxygen levels – in combination with DHT – dramatically increases androgen receptor activity. In fact, it increases androgen receptor expression six-fold versus DHT alone.

Why is this interesting? Well, an enlarged prostate and men’s balding scalps have a lot in common.

For one, our prostates and our balding scalp regions both use the enzyme type II 5-alpha reductase to convert free testosterone into DHT – and not other forms of 5-alpha reductase.

In addition, high DHT levels are associated with both balding scalp regions and an enlarged prostate.

But even more interesting? Hypoxia (lower oxygen) is associated with both prostate cancer and regions of the scalp which are balding.

Could the increased DHT we see in balding scalps somehow be connected to hypoxia? Probably. Especially when we consider how androgen receptors, in the presence of DHT and hypoxia, express 6-fold higher than in the presence of DHT alone.

What does all this mean? We can probably reduce DHT levels by decreasing androgen receptor expression. And how can we do that? By increasing oxygen tissue levels.

If We Increase Scalp Tissue Oxygen, Can We Reverse Hair Loss?

The evidence on oxygen therapies and DHT levels is limited, and the evidence on oxygen therapies regrowing hair is even more limited.

It’s not because the relationship doesn’t exist. Rather, it’s just under-studied.

Anecdotally, I’ve spoken with two people who tried hyperbaric oxygen therapy and said that it regrew their bald vertexes over a period of four months. And there’s also a patent on injectable ozone for hair loss sufferers, with cited case studies.

With that said, there’s not enough evidence to say with certainty that increasing oxygen is a viable option for 1) reducing androgen receptors, 2) reducing DHT levels, or 3) regrowing hair. There’s anecdotes, but no hard data.

Another challenge with oxygen: delivery. Just because we inhale pure oxygen doesn’t mean we actually raise tissue oxygen levels. This is probably why future hair loss therapies using oxygen will come in the form of injections rather than hyperbaric chambers – if at all.

But the bottom line: if we increase tissue oxygen levels, my bet is that this will 1) decrease androgen receptor activity and 2) encourage hair regrowth.

So let’s summarize our mechanisms (so far) for decreasing androgen receptors:

This brings us to our last mechanism to reducing androgen receptors: blocking them. And if you’ve tried many hair loss drugs or keep up with hair loss research, there’s a good chance you know what’s coming.

#3: Blocking Androgen Receptors

What does it mean to block androgen receptors?

In simple terms, it means to bind something to an androgen receptor so that the androgen receptor is “blocked off” from binding with actual androgens, like testosterone or DHT.

That’s how androgen receptor blockers reduce DHT: the AR blockers bind to a cell’s androgen receptors and prevent DHT from binding to that same cell. In effect, that DHT can no longer influence that cell’s function.

Androgen receptor blockers come in two forms: steroidal and non-steroidal. And like steroidal 5-alpha reductase inhibitors, steroidal androgen receptor blockers are also synthesized from hormones like progesterone.

#1: Steroidal Androgen Receptor Blockers – Spironolactone

When it comes to hair loss (and reducing DHT), the most popular androgen receptor blocker appears to be a drug called spironolactone (branded as Aldactone). This is an androgen receptor blocker derived from the hormone progesterone.

Spironolactone reduces DHT by blocking androgen receptors, and doctors often prescribe an oral form for women suffering from female pattern hair loss or even hirsutism – unwanted body and facial hair growth. This is because increased DHT is associated with hair loss in the scalp, but ironically, hair growth in the body and face.

But spironolactone is a powerful anti-androgen. In fact, most men are advised against taking it orally as a hair loss treatment. Why? Because it’s feminizing. In fact, oral spironolactone is the same drug some men use to transition genders and become female.

The good news for male hair loss sufferers? Spironolactone also comes in topical form – so we can concentrate its anti-androgen receptor effects to our scalps and minimize the risk of feminization.

So, if you’re a man and considering reducing scalp DHT by blocking androgen receptors, I would choose topical spironolactone over oral spironolactone.

With that said, spironolactone still comes with risks.

The Risk: Steroidal Androgen Receptor Blockers (Like Spironolactone) Activate Androgen Receptors… And Can Be Overpowered By DHT And Testosterone

 

Let’s break this down.

Each cell often has many androgen receptors. But not all of these androgen receptors are always active. In fact, in order for an androgen receptor to activate, they often need the presence of actual androgens – like testosterone or DHT.

Spironolactone is derived from steroids – or in other words, androgens. And as a result, our bodies read the presence of spironolactone as they would testosterone or DHT. And the response? To activate androgen receptors in cells where spironolactone is nearby.

This isn’t necessarily a huge problem… because in a perfect world, spironolactone would bind to all of those androgen receptors and render them unusable. However, there are two caveats.

The first: spironolactone may not bind to all the androgen receptors it activates.

And the second: steroidal AR blockers like spironolactone aren’t strong androgen receptor blockers. In fact, in the presence of too much DHT, spironolactone might dissociate from the androgen receptor it’s supposed to block, allowing androgens like DHT to come in and bind to that same androgen receptor.

Do you see the problem here?

  1. Spironolactone can activate many androgen receptors
  2. Spironolactone then binds to some of those androgen receptors
  3. …But if too much testosterone or DHT is nearby, it’ll also bind to those other activated androgen receptors. And in some cases, those androgens can dissociate spironolactone and then attach the androgen receptor it just activated!

The result? DHT flooding. And this isn’t theoretical. It’s been documented.

Some men taking steroidal AR blockers to treat an enlarged prostate inadvertently end up increasing the weight of their prostate (prostate growth) during treatment.

Moreover, some steroidal AR blockers can accelerate the growth of prostate cancer – the exact opposite of their intended effects.

This is why, for men especially, steroidal AR blockers like spironolactone are finicky, tricky drugs – especially for the purpose of DHT reduction and to fight hair loss.

This is why researchers’ focus on androgen receptor blockers – at least lately – is all about finding good non-steroidal androgen receptor blockers. And there might be a few good contenders.

#2: Non-Steroidal Androgen Receptor Blockers – RU58841

Aside from not being derived from hormones, the major difference between steroidal vs. non-steroidal androgen receptor blockers is that non-steroidal AR blockers are what we call “silent” androgen receptor antagonists. In other words, they block androgen receptors without actually activating them.

This makes them, in my opinion, a better option for anyone trying to fight hair loss by reducing DHT through androgen receptor blocking.

And remember those unintended, DHT-flooding effects of steroidal androgen receptor blockers? Based on the evidence, non-steroidal AR blockers don’t evoke the same response. They don’t likely cause growth in either the prostate or prostate cancer.

Two examples of non-steroidal androgen receptor blockers for hair loss?

  1. Flutamide. Historically, this drug was mostly geared for female pattern hair loss sufferers and men with advanced stage prostate cancer. But recent advents in topical delivery via nanoparticles might make this drug effective for hair loss – and maybe even devoid of major side effects.
  2. RU58841. In the past few years, RU58841 made the rounds on hair loss forums, but it has yet to legally make it to the US market (technically, you can still get your hands on it – albeit for “research” purposes only).

The side effects of non-steroidal androgen receptor blockers aren’t fully understood, so unfortunately I can’t say much. What I will say: when it comes to any anti-androgen – do your research, understand the risks, and exercise caution.

Now let’s add all of this to a flowchart:

 

Reduce Androgen Receptors: Summary

When it comes to reducing DHT by decreasing androgen receptors, there are three major ways we can go about doing this:

  1. Decrease total androgen production
  2. Decrease androgen receptor expression
  3. Block androgen receptors

Here’s a summary of the major mechanisms behind each way:

Unfortunately, when it comes to fighting hair loss, not all of these AR-reducing mechanisms hold promise.

For instance, the consequences of reducing DHT by reducing total androgen production far outweigh any potential benefits to our hair health. In addition, using steroidal androgen receptor blockers may evoke feminization or potentially lead to DHT flooding of the prostate and scalp tissue – the exact opposite of what we want to achieve.

So what does hold promise? It’s hard to say. But from the looks of it, I think more research should be done on increasing oxygen levels and non-steroidal androgen receptor blockers. Those mechanisms appear to have fewer side effects, but may be extremely powerful in reducing tissue DHT levels (and potentially reversing hair loss).

So let’s add these discoveries to our master flowchart, which is just one article away from completion. (The chart is getting big, so click on it to enlarge!)

What’s Next…

When it comes to reducing DHT in hopes of stopping hair loss, we’ve covered…

  • Free Testosterone
  • 5-Alpha Reductase
  • Androgen Receptors

But there’s still a fourth DHT-reducing pillar we haven’t discussed. What is it?

Increasing DHT metabolism.

In fact, research in increasing DHT metabolism might hold promise for hair loss sufferers looking to decrease scalp tissue DHT but avoid the sexual side effects of DHT reduction. This is all covered in the next (and final) article – where we will complete our Master Guide To The Mechanisms Behind DHT Reduction.

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Comments 14

  1. Pingback: Attacking DHT: A Master Guide To Inhibiting 5-Alpha Reductase — Perfect Hair Health

  2. Danny Roddy talked about CO2 being one of the factors of hair growth, we could achieve this by practising breathing through our noses only (Buteyko). Have you heard about this?

    1. Post
      Author

      It’s possible that deep breathing (Wim Hof exercises) or even elements of Buteyko (nasal breathing) could help. I think the real issue though is oxygen delivery to the affected scalp tissues. Just because we increase blood oxygen levels, doesn’t mean we’ll increase oxygen levels of chronically inflamed tissues. And while you’d think this would be more studied, it’s not! Which is disappointing…

      But the oxygen-hair loss connection seems pretty evident. For instance, just look at this review on chronic wounds and all the growth factors upregulated as a result of reduced oxygen: MMP2, MMP9, transforming growth factor beta… all the typical signaling protein players that we also see in pattern hair loss:

      http://www.medscape.com/viewarticle/727614_3

      I’ve read a bit about CO2 (I remember one of Danny Roddy’s articles from a while back on CO2, neonatal pattern hair loss, and CO2 as an opposer of the effects of prolactin). I don’t think there’s strong enough evidence to say with certainty that CO2 therapies will help with hair loss, but they’re certainly worth trying. I know of a few people who’ve used bag-breathing as part of a “kitchen sink” approach to hair regrowth – and with some success. It’s hard to say how much of their hair growth came from CO2 versus the dozens of other things they were doing – but we still can’t rule it out.

  3. Hi Rob

    Thanks for your interesting articles

    I don’t have hair loss :)) but I have increased DHT (1.5 times above the upper border). Also I have high T level (the doctor says too high for my age and I’m 51). I have been taking levitra (similar to viagra) on a regular basis during the last year (~twice per week). Do you think it may have increased DHT?

    The doctor does not believe it…

    1. Post
      Author

      Hey Yuri,

      Thanks for reaching out. With high T and DHT levels, I’m not surprised that you’re not dealing with any hair loss! Evidence suggests that serum (blood) DHT is uncorrelated with, or even protective against, pattern hair loss! I’m guessing your doctor measured your serum DHT, and not necessarily your tissue or saliva levels.

      https://perfecthairhealth.com/men-stop-thinking-your-hair-loss-is-due-to-high-testosterone/

      From my understanding, Levitra is a PDE-5 inhibitor. There’s little to no research on PDE-5 inhibitor’s effects on testosterone and DHT levels (at least that I could find). But interestingly, it appears that when it comes to treating erectile dysfunction, a PDE-5 inhibitor + testosterone therapy appears to work better than PDE-5 inhibitors alone.

      https://www.ncbi.nlm.nih.gov/pubmed/25643866

      With that said, it’s still unclear whether PDE-5 inhibitors effect T or DHT levels. But in my opinion, it shouldn’t be out-of-question.

    1. Post
      Author

      Those ingredients all might help with hair loss, but I’m not in love with the product. For one, you could buy all those indredients individually and mix them yourself for a fraction of the price $123.00. They’re all easily sourced from Amazon.

      Secondly, that sites claims 25,000 daily users of their product. I don’t see a single before-after photo. Just stock photography. Not to say that stuff wouldn’t work, but I’m of the belief that if a program or topical can regrow hair, and if you have thousands of customers, you also better have visual validation. I’d say save your money!

  4. Pingback: Attacking DHT: A Master Guide To Increasing DHT Metabolism — Perfect Hair Health

  5. Hi Rob,
    impressive research. Impressive communication skills.

    I would like to come back to the idea that DHT is actually a hair growth promoter (to all body and scalp hairs). This said to explain the hair loss on scalp is not a problem :
    – pressure increase in the scalp by : gravity + loose of quality of the connective subcutaneous tissue between skin scalp and Galea = oxygen and nutriments missing = triggers the over-expression of the DHT androgen receptors of follicles (the mecanism is a call for hair growth stimulatin, .. but unfortunately in excess and during many years, leading to overproduction of hair and exhausting effect, leading to follicle miniaturisation. This point is documented by a scientific paper, i can send you the one if your are interested.

    So to me, the point is how to TEMPORARY decrease (a little) the excess of DHT into scalp to calm down the bad cycle, and clean the scalp. Then in a second phase, the idea is to re-thicken the scalp subcutaneous layer in order to recreate the proper equilibrium of oxygen, blood flow, androgen level and AR susceptibility. The body is actually well made and capable to adapt.
    I would like to discuss further this point with you, please send me a private email address I can write to you to further expose my point of view and my analysis.

    Rob, I am sure I have here the key of the root cause of hair loss, but I am not saying I have the key to counteract it. Nevertheess with the knowledge I have today, I would have behaved differently at age of 20 for my scalp health.

    BR
    Patrice

    1. Post
      Author

      Thanks for commenting Patrice!

      I think I’ve seen the paper to which you’re referring – The Gravity Theory Of Baldness. There are a few alternative theories to pattern hair loss that I’m sure you’ve come across in your research. I broke down the major ones here, and also brought to light a few major holes in each theory:

      https://perfecthairhealth.com/the-leading-theories-of-pattern-hair-loss/

      I know you’ve commented on that post so I’m assuming you’ve also read through it. Just wanted to share with those who are following your comments.

      I agree with your sentiments about DHT, since tissue DHT in the body and face are associated with hair growth, and the only place in our body where DHT encourages hair loss is in the scalp. This suggests that DHT + at least one more factor trigger scalp hair loss. I took this theory as far as I could here:

      https://perfecthairhealth.com/the-ultimate-hair-loss-flowchart-why-we-lose-our-hair/

      The reality is that we haven’t done enough research into the etiology of hair loss to take this any further. Which is unfortunate – especially when we consider how much money goes into hair loss treatment developments (in the US especially, doctors try to treat the disease first without every fully understanding its causes).

      I’m happy to have a conversation. You can get my email address by signing up in an opt-in anywhere on my site. But I would like to keep the dialogue going in the comments, too. Readers of this site are typically very scientifically literature. They enjoy reading new ideas, and as a result, I’m sure they’d also love to read yours.

      Best,
      Rob

      1. This is an interesting concept, coupled with the hyperbarric oxigen chamber idea, and dilating blood vessels being propagated, perhaps the cells are starved and somehow induce inflammation for that reason, but I dont want to jump anywhere without research that could validate it. it is also worth noting the parts of the scalp that have muscles dont experience balding.

        there are methods that induce high blood pressure in the scalp area for short periods once a day that are used to grow hair at an accelerated rate and have worked surprisingly well for me personally. It would stand to reason to consider the opposite to be true too.. less blood flow less growth.

        there is a product by the name if Acell that has a strong concentration of healing compounds that is used with great success in wound repair as well as to greatly increase the success of hair transplants. Iv heard of a practitioner in LA that uses this compound with PRP to regrow hair, He seems to have a legitimate following and I have seen very poor results from PRP alone elsewhere.

        There are other compounds such a peptides ie. BCP-147 that have excellent healing properties and are known to encourage new capillaries to form in the injection site for upto 15cm

        I tried years ago to order Acell and was refereed to a distributor with no interest in supplying.
        Im hoping to try again soon

        to get to try any of these solutions you would need to find yourself a one in a million doctor who would likely charge half the price of a small car. its a sad reality

      2. Post
        Author

        Thanks for the comments, Nick. And I agree – the prices of some of these treatments (regardless of their success rates) are far too expensive. I’ve had several readers who’ve paid several thousand dollars for a series of PRP + Acell treatments only to report increased shedding. It’s a frustrating reality for most hair loss sufferers.

        I’ll look into BCP-147 and get back to you. And if I hear of any practitioners offering hyperbaric oxygen chambers at an affordable rate to treat calcification, fibrosis, or other hair loss-related conditions, I’ll be sure to reach out.

        I’m heading to Los Angeles in two months (I’ll be down there for at least a few weeks) and will try to track down that practitioner to hear what else he’s doing differently. If he allows me to share anything, I’ll be sure to post it on the site.

        Best,
        Rob

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