Morning everybody!

I had a great question land in the HRTU private community the other day.

I'm paraphrasing, but it went something like this...

"Nico, my patient's hematocrit is at 52. Should I do a therapeutic phlebotomy?"

And here's my honest answer: no... but there's some nuance here.

Let me explain what I mean.

A paper just published in Endocrine Connections asked a question that the field has been quietly avoiding for years.

Is therapeutic phlebotomy for TRT-induced erythrocytosis actually safe?

And the answer the literature gives us right now is: we genuinely don't have enough evidence to say yes.

Here's what we do know.

TRT causes secondary erythrocytosis.

That's a normal, physiological finding. Testosterone raises EPO initially, establishes a new EPO/hemoglobin set point, and suppresses hepcidin, which increases iron availability for red cell production.

The body lands at a higher hematocrit. That's just a normal recalibration, not a disease process - not pathology.

And importantly, the TRAVERSE trial, the largest RCT of TRT to date with over 5,200 men, did not find a significant increase in VTE.

No meaningful thrombotic signal.

So where did the phlebotomy reflex come from?

Polycythemia vera.

In PV, phlebotomy to a hematocrit target below 45% is standard of care. It works. Thrombosis is the major cause of morbidity in that disease.

But here's the problem.

PV is a myeloproliferative disorder. The thrombotic risk in PV dwarfs what we see in secondary erythrocytosis. The mechanisms are different. The pathophysiology is different. And we just borrowed the treatment without ever asking whether the logic actually transferred.

That's a pretty big assumption.

Now here's where the paper gets really interesting.

Phlebotomy doesn't just lower a number. It depletes iron stores. It lowers tissue oxygen levels. And both of those things activate a pathway that, once you understand it, changes how you think about this entirely.

Here's the simplest way I can put it:

Think of your body's oxygen-sensing system like a thermostat in your house.

When tissue oxygen drops, the thermostat reads "cold" and cranks up the heat by producing more red blood cells.

That's the normal physiological response.

Phlebotomy lowers your hematocrit, which also lowers tissue oxygen. So the thermostat reads cold again. And when iron stores get depleted on top of that, the off-switch for the thermostat stops working properly.

Now you've got a thermostat stuck in the "on" position.

The problem is that same "on" signal also activates clotting factors.

So you lowered the number on the lab. But you may have made the underlying biology worse.

This is the HIF pathway, or hypoxia-inducible factors, for those of you who want to go deeper. When tissue oxygen drops, HIF-alpha stabilizes. And persistent HIF elevation has been linked to increased expression of tissue factor, thrombospondin, and other proteins that directly increase clotting risk. The enzymes that break down HIF-alpha require iron as a cofactor, so once iron gets depleted through repeated phlebotomy, that off-switch becomes even less effective.

The authors even draw a comparison to Chuvash erythrocytosis, a congenital condition where phlebotomy is specifically contraindicated because it increases clot risk through this exact mechanism, independent of what hematocrit does.

Different condition, yes, but the mechanistic overlap is really interesting.

So what did the authors conclusion come to?

What this does not mean...

This is not a claim that phlebotomy is always dangerous.

The paper makes a reasonable distinction. One or two phlebotomies alongside a dose reduction, to accelerate hematocrit correction while the dose adjustment takes effect, is probably low risk. You have a clear reason, a clear endpoint, and a clear exit.

The concern is chronic, repeated phlebotomy used to keep hematocrit suppressed when dose reduction alone isn't doing the job. That's where iron depletion and that stuck thermostat become clinically relevant.

And this is not an argument to ignore hematocrit entirely. Observational data does suggest that hematocrit at or above 52% on TRT may track with higher rates of MACE and VTE, though causality is unproven and the populations studied had significant comorbidities.

These are associations. Treat them like associations.

So what should you do?

Oftentimes, you don't need to do anything if no clear pathology exists.

You can explore dose reduction and/or changes in administration first (I go deeper into this in the Male HRT Module).

You should also address modifiable risk factors like smoking and obstructive sleep apnea, obesity, dehydration etc. This is almost always the biggest lever.

If you do proceed with phlebotomy, do it in shared decision-making with your patient, and be honest that the safety and efficacy data is thin.

There's no validated cutoff that makes phlebotomy right or wrong for a TRT patient. That uncertainty is not a failure on your part, but just a lack of clear literature.

It means we likely borrowed a treatment from a different disease and called it standard of care without doing the work to prove it belonged here.

Hope this helps.

-Nico

PS

If you want to develop the kind of clinical reasoning that lets you navigate these gray zones confidently, that's what we build inside the Master Course. Six modules, 30 CEUs, and a framework that helps you think through cases when the guidelines don't have a clean answer.

hrtuniversity.com/hrtcourse

PPS

Check out the latest HRT University Podcast episode on early puberty, xenoestrogens. You will hear why exposure history and age of menarche belong on your intake form, why some patients fail progesterone because of receptor competition rather than dosing, and how to run the exposure-reduction conversation so the hormones you prescribe can win at the receptor.

Listen now on Spotify, Apple Podcasts, and YouTube.
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