Why injected HRT?

Why injected HRT?

There was an interview on RNZ’s Nine to Noon programme this morning about why transgender patients are turning to DIY HRT. They had one of the doctors who works on the New Zealand gender-affirming healthcare standards on and her answers were infuriating to say the least. The mental leaps to go “we don’t prescribe injected HRT, therefore we don’t know its safety, therefore we don’t prescribe it” is astonishing, and her lack of acknowledgement of overseas experience just iced the cake.

That said, I decided to write down why injected oestrogen is different to the currently available patches and pills. This post contains maths!


In a nutshell, bioavailability. This is the term for how much of a medicine you take actually makes it in to your body in an effective form. For example, paracetamol has a bioavailability of 63-89%1. Why the range? Everybody’s different, some people absorb more than others, and some people have a more efficient liver.

So lets look at bioavailability of oestrogen, and I’ll include maths on my levels.

How much oestrogen do you need daily?

This has two factors, the target level in your blood, expressed in picomoles per litre (pmol/L) of blood, and the metabolic clearance rate. The metabolic clearance rate is the rate at which your body removes the substance from your blood, expressed in litres of blood that will be fully cleansed per day.

We’re interested in estradiol, since that’s the type of oestrogen used in most feminising hormone therapy. There’s no consensus on what a good target level is, so I’ll pick 350pmol/L. NZ standards say 700pmol/L is the upper limit 2, 350 is half that and co-incidentally (or not) the level I could achieve on oral oestrogen.

Annoyingly while estradiol is measured in moles per litre the medications are measured in grams, so we have to do some maths… The molar mass of estradiol is 272.388g/mol3, and the typical adult has around 5 litres of blood, for a total of 1,750 picomoles of estradiol, or 1.75×10-9 moles. Doing the math gives 4.7668×10-7g, or 476.68nanograms of estradiol total. Wikipedia says the metabolic clearance rate of estradiol is around 1200L/day, and given the previous calculation this means that 12005×476.68ng=114,403nanograms of estradiol, or 114.4µg, per day would be needed to balance out the metabolic clearance rate.

Actually that would leave you with zero oestrogen, so lets make that 114.8µg to make sure there’s enough left at the end.

OK, what’s the point of all this?

Oral oestrogen (pills)

The main oestrogen in pill form in NZ is estradiol valerate. You can also get estradiol hemihydrate, but that’s only partially funded. When I was taking the pills my blood estradiol levels were around 350pmol/L, varying between 330 and 370 probably due to time since the dose.

I was taking 6mg daily. 6mg, for an active amount totalling 114.8µg for the day. That’s 1.9%. 1.9% of the total estrogen I was taking was making it in to my bloodstream to have an effect. And yes, this is the expected amount, the documented bioavailability is <5%.

Why? The liver! All the blood that runs through your digestive system gets directed through your liver to remove anything toxic. One of the things your body really wants to keep out is hormones, and your liver is extremely good at this! (not as good as a hamster’s liver with alcohol, but that’s another topic). This means the only way to get estradiol in to your body orally is by taking so much that your liver simply cannot process it all, this isn’t dangerous to your liver but can interfere with metabolism of other drugs.

Also the pills are instant release, with a peak immediately following taking them which drops off by the next day. Having hormones do this isn’t great for your mental health, and the peaks do mean oral oestrogens have a higher risk of blood clots than other methods.

Transdermal (patches)

Patches bypass the liver by using allowing the estradiol to diffuse through the skin in to the bloodstream, consequently the bioavailability is higher, and also the level is more stable because they release medication continually.

I’m on a 200µg/day patch at the moment (actually two 100µg/day patches because 100µg is the highest dose they make) and this gives me an estradiol level of 450nmol/L. Lets re-do the math above. 450×10-12mol/L×272.388g/mole×1200L/day. That gives 147µg/day, a bit shy of the 200µg they claim!

200µg in a Standard Human would give 600pmol/L, but there’s no such thing as a standard human. My liver might process a bit faster, I might have a bit more than 5L of blood, or my skin might be slightly less porous. Also despite being a more continuous dose patches still have an initial peak and slowly drop over their treatment window.

So what about bioavailability? The datasheet for the patches states they contain 1.64mg for the 100µg per day delivery, and they last 3.5 days. So of the 1.64mg, 0.3mg is effective, or about 18%. Ten times higher than pills!

And the downside? The glue! The glue is awful, it’s very hard to remove (rub baby oil in to it before you shower) but if you don’t it will irritate your skin, and some people have reactions to the adhesive. Also you can sensitise over time, which would force you to stop using patches.

Gel-based formulations have the same absorption issue, just no glue.

Interestingly the oestrogen is in the adhesive, getting oestrogen in to and out of plastic is extremely difficult.

How is this about injections again?

Intramuscular injected oestrogen is 100% bioavailable. If you listen to the doctors in New Zealand they’ll tell you that injected oestrogen results in supra-physiological peaks which increases the risk of blood clots, and they’re not wrong. However they’re ignoring the fact that this isn’t the case for all estradiol esters - compounds that contain estradiol that the body metabolises over time to release the oestrogen.

Levels of estradiol over time for various esters Lets look at the graph to the left sourced from Wikipedia4 and you will see that estradiol valerate has high peaks and is gone very fast, needing frequent injections. However the cypionate and enanthate esters have a much slower release profile, only needing injections every two weeks. This is not new research, the Wikipedia citations show it’s from the 1980s and 1990s! (Ignore the units, the USA uses pg/mL rather than pmol/L)

The slow and consistent release profiles of appropriate estradiol esters also allows for another possibility - monotherapy. Oestrogens are anti-androgenic, but the levels required are higher than is safe with patches or pills. For some people an oestradiol level of 600-700pmol/L - still within the known physiological levels - is enough to suppress testosterone levels without any anti-androgen, and anti-androgens have more side-effects than bio-identical oestrogen.

So the downside? You have to inject it every 10-14 days, assuming cypionate or enanthate esters. However type 1 diabetics have been self-injecting insulin for decades now, this is a solved problem. The other one, only estradiol cypionate is manufactured commercially and is not approved in NZ. See my post about Medsafe for more detail on that. Both estradiol cypionate and enanthate can be sourced from a compounding pharmacy though.

What about synthetic oestrogens?

Synthetic oestrogens are manufactured analogues of natural oestrogen. They can be tailored to bypass liver metabolism while still interacting with the oestrogen receptors in the body, a good example is ethinylestradiol which is widely used in contraceptive pills. Synthetic oestrogens aren’t considered a good option for transgender hormone therapy as they don’t bind to oestrogen receptors in the same proportion as natural oestrogens. While this isn’t a problem if you have plenty of your own oestrogen when you’re relying entirely on exogenous hormones this could present an issue. We know how bio-identical hormones work, because everyone alive has them!


Wikipedia - estradiol. Yes I know you shouldn’t cite wikipedia but it has sources if you want!


Pharmacokinetics of estradiol, Graph by Medgirl131 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=71306500


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