Read time: 10 minutes
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.
- Decrease free testosterone
- Inhibit 5-alpha reductase
- Decrease androgen receptors
- …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!
- Decreasing androgen receptors, and…
- 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).
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…
- Decrease total androgen production
- Decrease androgen receptor expression
- 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?
- Spironolactone can activate many androgen receptors
- Spironolactone then binds to some of those androgen receptors
- …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?
- 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.
- 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:
- Decrease total androgen production
- Decrease androgen receptor expression
- 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!)
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?
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.
Rob English is a researcher, medical editor, and the founder of perfecthairhealth.com. He acts as a peer reviewer for scholarly journals and has published two peer-reviewed papers on androgenic alopecia. He writes regularly about the science behind hair loss (and hair growth). Feel free to browse his long-form articles and publications throughout this site.