Dr. Rhonda Patrick: The last topic to get to, which we've already touched on, is one of the potential side effects of androgen or hormone-replacement therapy: hair loss. I know you've talked about this personally. Why does hair loss occur, and what is the role of DHT in that process?

Derek: It's crazy that today we have advanced artificial intelligence and cutting-edge treatments that can nearly eliminate ASCVD risk by lowering ApoB, but with hair loss no one has a clear idea how to prevent it without reducing DHT levels. As long as I've researched this, people have said a solution is on the horizon. Every two weeks there is a viral article about scientists regrowing hair in rodents with some random compound, and people on Reddit put unusual things on their heads.

Dr. Rhonda Patrick: Sulforaphane was one at one point. People were putting broccoli sprouts on their heads.

Derek: That did not end up working. There are adjunct treatments once you attenuate the follicle miniaturization caused by androgen activity in the scalp. Ketoconazole shampoo is a mild antiandrogen that might add protection if, for example, someone uses finasteride rather than the more potent dutasteride because that risk profile suits them better.

Ketoconazole can help. Studies have reported hair-growth results similar to 2 percent minoxidil through a different mechanism, which is notable for an over-the-counter shampoo. It can also reduce dandruff and improve seborrheic dermatitis and the scalp environment. It acts as a mild 5-alpha-reductase inhibitor and topical antiandrogen. It is useful as a shampoo with a lower risk profile than finasteride or dutasteride, but for most people it will not be enough by itself to offset androgen-driven hair loss unless they are only mildly susceptible. That is where pharmaceutical 5-alpha-reductase inhibition may be added.

Minoxidil is an FDA-approved growth stimulant that works reliably for many people, but the response depends on enzymatic conversion. It must be converted into minoxidil sulfate in the scalp. A person with low sulfotransferase enzyme activity can be a nonresponder even when using the full dose every day. Other potential problems include an unhealthy or unclean scalp environment, inadequate delivery, insufficient dose, or the formulation itself.

Once those issues are addressed, sulfotransferase activity can still limit the response. One approach is to compound minoxidil with tretinoin, which can upregulate the enzyme and allow more conversion. Microneedling can also turn some nonresponders into responders or magnify results. That may involve better absorption, greater sulfotransferase activity, or growth factors recruited by controlled microinjury. There are even reports of hair regrowth after scalp burns, although obviously no one should light their head on fire.

Dr. Rhonda Patrick: What are the side effects of topical minoxidil?

Derek: Minoxidil was originally prescribed orally for high blood pressure as Loniten.

Dr. Rhonda Patrick: Oral minoxidil? I thought it was topical.

Derek: When it was prescribed for blood pressure decades ago, side effects included fainting on standing, low blood pressure, water retention, and substantial hair growth, including on the scalp. That led to repurposing the drug as a topical hair-growth treatment. Topical delivery appears to avoid much of the systemic side-effect profile of oral minoxidil.

Some dermatologists still prescribe oral minoxidil. It is a potent, older blood-pressure drug with a black-box warning. The liver has substantial sulfotransferase activity, so oral minoxidil produces systemic minoxidil sulfate. Potential systemic effects include pericardial effusion, water retention, electrolyte dysregulation, and effects related to potassium-channel opening. Even at low doses, some people report arrhythmias or chest pain. Oral minoxidil can work well, but topical minoxidil is the more conservative entry point. It is available over the counter and is less likely to produce systemic effects.

Many studies show benefit from topical minoxidil. The main drawback is that it must be applied consistently. If efficacy needs to be increased, someone might discuss compounded tretinoin or microneedling before considering the greater systemic exposure of an oral formulation.

Dr. Rhonda Patrick: Is tretinoin oral or topical?

Derek: Topical. A compounding pharmacy would formulate it with minoxidil because that combination is not sold over the counter. If it were me, I would start with topical minoxidil. If I had no response, I would look at microneedling to improve absorption or influence enzyme activity before adding another drug.

Microneedling is controlled microdamage that might be done once a week. Some newer literature suggests a depth of 0.6 millimeters might work, whereas older studies used 1.5 millimeters, which was likely to draw blood. Some of my older YouTube videos show a bloody scalp because of the depth I used. A shallower depth may have less cosmetic impact and a faster recovery. There could still be downstream issues from needling the scalp every week, but the data and my own experience have been reassuring so far. I would consider compounded tretinoin and minoxidil after that if needed.

Dr. Rhonda Patrick: I'm interested in microneedling for its effects on skin.

Derek: People use it on their faces too.

Dr. Rhonda Patrick: It is something I'm going to do. My dermatologist conducts research, and the clinic brochures had a whole hair-loss section about microneedling and stem-cell growth factors. I asked what was happening, and she said they had done a small study using a combination of growth factors involved in hair-follicle stem-cell production.

That is why I was interested in microneedling for hair. I wondered whether the main effect was improving absorption, because applying growth factors to the intact scalp might not deliver them effectively.

Derek: I think most of the benefit is likely from ensuring adequate absorption of minoxidil. When you compare microneedling alone, minoxidil alone, and microneedling plus minoxidil, microneedling alone does not produce the outcome you would expect if local growth-factor recruitment were the major driver. It appears more likely to help the drug reach its target.

That is still useful if absorption is what someone needs. Some studies have reported several-fold greater results with the combination.

Dr. Rhonda Patrick: That seems like a legitimate path for men who are concerned about potential side effects from oral drugs. You mentioned finasteride. What is the other one?

Derek: Dutasteride.

Dr. Rhonda Patrick: Are there serious side effects from finasteride or dutasteride beyond sexual function?

Derek: Potentially neurological effects through changes in neurosteroids. There is a large area of research around inhibiting allopregnanolone, which contributes to GABAergic, anxiolytic signaling and has been implicated in postpartum depression. A pharmaceutical form was developed to restore this signaling in women with postpartum depression. By inhibiting 5-alpha-reductase, these drugs may reduce that calming neurosteroid pathway.

The effect depends on the person and can be severe. People discuss post-finasteride syndrome.

You rarely hear the phrase post-dutasteride syndrome even though dutasteride is a more potent drug, which suggests that media framing influences reporting. That does not mean the side effects are not real. These drugs can cause side effects, but a substantial nocebo effect may also occur. Someone can read what might happen, become convinced it has happened, and experience real symptoms because of that expectation.

Dr. Rhonda Patrick: The nocebo effect is real. There are single-nucleotide polymorphisms, or SNPs, associated with susceptibility to placebo and nocebo effects, and some are measured by 23andMe. Some people may be more susceptible to expecting benefit or harm. I take creatine and think, "Yes, I'm not getting sleepy in the afternoon." It could be placebo, but the perceived effect is still real to me.

Derek: One clarification about minoxidil: it is a growth stimulant. It does not attenuate follicle miniaturization caused by DHT. Preventing that miniaturization requires lowering androgenic activity, perhaps with mild ketoconazole, finasteride, dutasteride, or a topical antiandrogen. Ketoconazole is useful and relatively benign, but it probably will not be sufficient for most people.

Minoxidil is used to regrow hair, not to prevent the underlying loss. The added growth can temporarily offset the visible loss, but miniaturization can eventually catch up and continue past it.

Dr. Rhonda Patrick: I see.

Derek: Minoxidil can still delay the visible effect for someone who wants to avoid inhibiting hormones. Hair transplants also buy time. If someone wants to address the androgenic process directly, they have to inhibit androgen activity in the scalp. In a mild exaggeration, you have to turn the scalp into a female scalp.

Dr. Rhonda Patrick: Interesting. And you're...

Derek: Mild exaggeration, but you got...