Everyone lucky enough to be prescribe progesterone in the form of oral micronised progesterone capsules has probably been told to ensure they take them on an empty stomach. This isn’t that uncommon with medications, eating can affect the way they are absorbed. Out of curiosity I wondered what the problems are, in case I forget and have a snack just before taking it.

First, a caution. Always take medication in the manner prescribed by your doctor. This information is just for curiosity.

It turns out there was a study done in 1993. Micronised progesterone for oral administration came to the market in 1980, so it’s been around a while and a lot of the studies are fairly old. It’s a well understood product.

The study¹ handily titled “The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone” was performed on 15 post-menopausal women, so it’s a very small sample size. To quote their results:

Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC_{0 to 24}) and the maximum serum P concentration (C_max) without affecting time to maximum serum concentration (T_max) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg.

So to translate that - taking your progesterone with food increases your absorption of progesterone, over the 24 hour period more total progesterone was absorbed, higher blood progesterone levels were measured, but the time taken to get to the maximum progesterone level was the same as for fasting. Secondly, the absorption of progesterone scales directly with dose, it doesn’t seem to drop down or rapidly increase.

But how much more progesterone is absorbed? From the paper’s conclusion:

Absorption of micronized P was enhanced twofold in the presence of food.

So taking progesterone with food results in twice the absorption rate compared to fasting. The peak is higher but the rate of metabolism is unaffected, so the end result is a consistently higher serum progesterone level (you can look at the paper to see the graphs and numbers)

Why are we told to take progesterone on an empty stomach? I can’t find an answer. It could be to avoid the peak - nearly six times higher when taken with food - or there could be other interactions not documented in this paper. If I find out more I’ll post an update!

One thing everyone who takes oral oestrogens, whether for contraception, menopausal HRT or gender-affirming HRT, gets told by their doctor is that oral oestrogen raises the risk of blood clots - called a thromboembolism in the medical world. However we’re never really told what the risk actually is. If the rate without the medication is 1 in 100,000 per year and the increase in risk is 10% - to 1.1 in 100,000 of people on the medication - then perhaps it’s not a problem? But if increase is to 50 in 100,000 - a 500% increase if I can do maths today - then that might be more concerning.

So let’s dig in to the literature again!

Summary (for the TL;DR)

Yes oestrogen HRT increases the rate of blood clots, but dose doesn’t make much difference when using bio-identical 17β-estradiol. The difference in risk of using pills, patches gels or injections is still not clearly understood. The rates reported are not adequately controlled for dose form, oestrogen type, and additional risk factors.

Synthetic oestrogen such as ethinyl estradiol have a much higher risk than bio-identical 17β-estradiol.

Overall the risk of HRT containing bio-identical 17β-estradiol is higher that the general population, but still a very low risk.

Does oestrogen itself increase blood clots?

While a study showing a correlation between oestrogen levels during pregnancy and blood clots has previously been widely circulated, a more modern study¹ shows that in the absence of oestrogen-containing medications sex hormone levels have no significant impact on rates of blood clots. Oestrogen levels during pregnancy are an order of magnitude higher than would be achieved by any form of medication.

So no, oestrogen levels are not the cause of blood clots, at least when in the normal physiological range.

The story is different with oestrogen-containing medications

Does HRT increase the rate of blood clots?

In short, yes.

The main clots that have been studied are venous thromboembolisms - VTE - which are clots that form in veins, generally in your arms and legs. We’re often told it depends on the dose level and route of administration - pills, transdermal patch/gel, injection or implant - with pills being the worst.

Fortunately there have been two studies performed on this recently! They are both meta-analyses, which means their authors haven’t done a direct study, but have identified previous good studies and combined their results. In particular they’ve found studies that not only recorded the rate of VTE, but also the type of oestrogens used, the dose, route of administration, and any other hormone medication used alongside. So many papers just say “transgender HRT has this rate of VTE” with no detail of what form, dose, or administration route is being used! This makes my job easier.

I’m only going to refer to one of the papers here, because it cites the other. I’ll link to both.

Publication: Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy ²

The paper I’m going to cite identified 13 studies that had observed the rate of VTE and also noted the form of oestrogen and dose used. I’m going to be a bit naughty and do a pull-quote from the results before discussing it more, to set the stage a bit

Finally, even if the risk from exogenous estrogen use remains significant statistically, the absolute clinical risk remains low.

In plain English - even if HRT causes an increase in blood clots which can be measured, it’s still a very low rate.

In depth

This analysis found that the synthetic oestrogen ethinyl estradiol causes a much larger increase in the rate of VTE than bio-identical estradiol. Synthetic progestins - such as cyproterone acetate - were also found to have a larger effect on VTE rate than estradiol valerate in any form.

The paper also says that:

Data suggest a positive correlation between estrogen use and VTE. A recent review³ found the overall incidence rate to be 2.3 events per 1,000 patient-years.

which cites the other paper - but there’s another point made. VTEs are associated with other health conditions and behaviours. Smoking tobacco is well known to increase the rate of blood clots, as are having high blood pressure, hypertension, undergoing surgery, and being HIV positive. Additionally acute stress and other mental health conditions are correlated with blood clot rates. From the paper:

Only one study to date demonstrates an occurrence of VTE in the absence of risk factors beyond hormone therapy.

That study⁴ followed 676 trans women over 8 years on predominantly oral oestrogen, and only had one incidence of VTE.

Their conclusion?

Firstly, avoid ethinyl estradiol containing medications. They have a significantly higher risk of blood clots

Secondly,

Although there seems to be clear evidence that transdermal estrogens dosed up to 0.1 mg/day or below are a lower risk for VTE than other forms of estrogen, it is unclear whether this is related to the delivery method or a dose effect.

0.1mg/day is a low transdermal dose. The current PATHA guidelines go up to 0.2mg/day, which has similar risks to oral estradiol valerate.

Risk mitigation is an important part of the care of transgender patients due to the many risks associated with not providing hormone therapy (ie, poor mental health) and the potential risks associated with hormone therapy. Further study of the relationship between estrogen and the risk of VTE will serve to inform the safest possible care for transgender patients

So as always, the conclusion is there’s not enough data to draw a solid conclusion, but treatment should be based on risk mitigation and acknowledge that focussing on risk minimisation may have worse outcomes for the patient.

So where are we?

Women not on any form of oestrogen medication have a VTE rate of around 4.2 per 10,000 person-years. With a rate of 23 per 10,000 patient-years according to that study that’s a large difference, but the analysis included use of synthetic hormones that are known to have far higher risk. They also noted that only one study identified a blood clot occurring without other know risk factors present - that paper gave a rate of 7.8 per 10,000 person-years.

Unlike menopausal HRT, the risks associated with different delivery mechanisms is not as clear-cut.

So yes, you will have a higher risk of blood clots on any form of estrogen and you should try to manage it through other factors you can control, such as not smoking and monitoring your health.

Short post time!

Basic biology says that having an XX or XY karyotype determines reproductive organs.

Intermediate biology says it’s the SRY gene, which is normally on the Y but can be on the X.

Advanced biology says we have no idea and it could be anything!

SRY-negative 46,XX male with normal genitals, complete masculinization and infertility

This is a post I’ve been trying to write for months, but it’s difficult to actually finish, or at least figure out the point I’m trying to make…

So I have ADHD. I was diagnosed 18 months ago, which at 38 makes it a rather late in life diagnosis. However now I actually know why my brain doesn’t work the way most people expect it to I have a whole new way of managing my life which has really changed things.

Most of my school years were in the 90s, and the prevailing perception of ADHD at the time was children, almost exclusively boys, being hyperactive and disruptive. This of course lead to the counter view by some groups of it being caused by “bad parents who just want to drug their children”. Neither of these views are correct, and both are very unhelpful. Needless to say despite it being suggested from a young age I never had any formal assessment or support.

I don’t have many symptoms of hyperactivity - though my psychiatrist did raise an eyebrow about that when I showed my health tracker reading over 4,000 steps on a work from home day when I didn’t go outside - but mostly inattention. The inattention side of ADHD is quite insidious as hyperactivity at least has external signs, but inattention is invisible to others, and yourself, until too late. For me this made school and university some of the worst times of my life, no matter what I tried from the ‘conventional wisdom’ I just got told over and over again to pay attention and work on time management skills, but nobody ever thought to teach me how. It turns out that that’s because most people just have those skills at some level, who knew?

And that’s the crux of ADHD for me - I’m not running around disrupting things, and I’m not just distracted. ADHD is an executive dysfunction. The executive - much like in a business - manages priorities. It doesn’t actively do them, but it determines what should be done when, for how long, and what the expected outcome is. If a business has a dysfunctional executive then supplies don’t arrive on time, they don’t make the right products at the right time, and important documents aren’t filed properly, or if these things are done they are done at the very last minute.

On the more social side, lack of prioritisation leads to lack of time perception. I don’t catch up with my friends not because I don’t want to, but because I fail to prioritise organising things until it becomes too socially awkward to do it!

Sound familiar? It certainly did to my life. No planning “life hack” worked, no organiser or list helped, because critically you have to prioritise using those, and when your whole problem is an inability for your brain to prioritise they are never going to work.

So what did help?

Certainly medication has helped, but ADHD medication is a double-edged sword. Which is an odd saying because a double-edged sword is definitely superior to a single edged one and both will cut you if you swing it at yourself, but I guess hilt-less makes even less sense? Anyway I digress. ADHD medication helps with inattention, but that’s all it really does. With medication you can focus on things and it’s harder to get distracted but it doesn’t really help with the prioritisation, so it’s even easier to focus on the wrong thing than before. Like writing this post when it’s time to cook dinner!

The real help for me was CBT, cognitive behavioural therapy. Like all forms of psychotherapy it’s not going to work for everyone but for me the focus on understanding why my brain works in the way it does was key. Now that I know it’s the prioritisation area that’s causing me issues I can work around that using a combination of calendar alerts, scheduled reminders, and routines. I’ve disabled almost every notification outside and made a habit of checking apps either at the end of a task or a certain time each day - no YouTubers, I won’t use the notification bell, I’ll just check the subscriptions page when I’m ready! I don’t get any notifications from Slack, or Facebook, or Discord, or any of the other sources that ping people constantly. This means I know if something notifies me it’s something I’ve already prioritised.

It still doesn’t help with things outside that, I have a huge todo list for my hobbies and keep finding new ones, but those aren’t causing (much) of a problem with my daily life.

And I guess that comes to my last point (have I made any points?). It’s not worth getting diagnosed if you don’t have any problems in your day to day life. However if your career is stuck in a rut, you’re having to pay late fees on bills because you just forgot to pay them, or your social life is suffering because you just forget to organise things, perhaps it’s worth talking to a specialist.

I’m still quite irritated that this wasn’t dealt with when I was young, with the knowledge of how to manage ADHD I might have done things other than software development, and certainly wouldn’t have had as many issues with anxiety. I’ll never know though, can’t change that so the only thing to do is improve things from now!

An article just appeared on the news that GPs consider self-requested medical testing “concerning and unnecessary”. Of course, I think they’re wrong, but I’m going to outline some reasons.

Firstly, a question to those against this. Why do people feel the need to self-request medical tests?

Tests requested by a medical practitioner are free, when you self-request they are not, often costing more than a GP appointment. Clearly people feel they are not getting the care they need - I have had my health concerns completely dismissed by GPs with no follow-up so understand why someone would get tests done by themselves.

I’m sure there’s a lot of misinformation out there are people getting unnecessary tests, but we should not remove a service just because some people use it - at their own cost - when they don’t need to.

So, back to why people self-request tests, and I’m going to start with a transgender perspective.

Transgender healthcare is frequently poor. I know people who’ve been ignored, gaslighted and outright lied to by the people supposed to provide the medical guidance for their transition, so to keep GPs honest they get their own tests. This should not be necessary, but it’s a reality for a lot of us. Most often this seems to be providing menopausal levels of oestrogen and refusing to do any tests, so by getting these tests people can find out what’s actually happening and change GPs. Without the ability to do self-requested tests there’s no way to double-check a GP’s opinion.

Secondly, “DIY” therapy - that is obtaining hormones illegally without a prescription - is not uncommon. This is often because doctors have refused to provide care, or won’t provide care the patient wants. Self-requested testing is used by DIYers to monitor their own levels, ensuring that they’re not exceeding appropriate levels and actually have medication containing the hormones they want. Why do they DIY? Simply because specialists refuse to prescribe injected oestrogen or any sort of testosterone therapy so people take it on themselves to get the medication, and sometimes because they’re refused an increase in dosage. I explored some of this in a post on considering DIY therapy.

Lastly, because people modify their treatment regimes without consulting a doctor. Perhaps increasing or decreasing an anti-androgen, or altering the time of day medications are taken. Getting this done with GP approval can be very hard, especially if your GP sticks rigidly to the guidelines and does not take your wishes in to account. Self-requested testing can help show if you’re on the right track or not, and to ensure your levels are at the GP-expected ones before a test they’ll see.

None of these tests would be self-requested if people got the care they want, but that can be very hard and costly to do - even when the cost of tests is taken in to account.

And for non-hormone tests?

Also sometimes it’s easier than booking an appointment with your GP and taking time out of your day to see them for a five minute request. When GPs are booked out for multiple weeks in advance getting a test when you know what you need can take too long. Sometimes your request would be declined, then you just wasted the cost of the appointment.

Personally I’ve done self-requested tests for hormone panels (and once for a blood type test, because while interesting it’s not medically important to know in advance), mostly to get data on medication timing and drop-off for my own curiosity, but also to check levels while using DIY progesterone before I found a GP who’d prescribe it properly.

Is there a conclusion?

Not really. Just my opinion that restricting people from obtaining their own medical tests isn’t going to help trust in the medical profession.

Have anything else to add? You can reply on the Fediverse - @blog@thea.hutchings.gen.nz - or via the comment form below.

Progesterone is by far the most controversial hormone in transgender HRT. Almost bizarrely so, the amount of clinical misinformation, dis-information, gaslighting, and just straight ignorance is astounding. So let’s look in to it!

Misinformation?

I’ve been told that progesterone has “no benefits”, which from personal experience is not true (“no proven benefits” is technically correct, but we’ll get in to that later), and others I know have been told that it’s “risky” - though without specifying the risks - and even that it’s a carcinogen, which would be pretty astonishing if true given that progesterone is part of every healthy human’s system!

What is progesterone?

Progesterone is a human sex hormone, like testosterone and oestrogen (yes there’s an oestrone, but oestrogen always seems to be used instead, perhaps because oestrone isn’t the most clinically important oestrogen). Biologically progesterone is the main precursor to testosterone, which itself is the main precursor to oestradiol.

The broader class of similar hormones is called progestogens, all progestogens have similar behaviour with varying degrees of potency, as do oestrogens (oestrone, oestradiol etc) and androgens (testosterone, dihydrotestosterone etc). There are also many synthetic progestogens, collectively known as progestins. These are often used in contraceptive pills, among other uses.

Progestogens play an important role in the reproductive system, it’s well known as the hormone that regulates the menstrual cycle but progesterone is also important for spermatogenesis and has effects on sleep, appetite, and the immune system¹.

For people with an active menstrual cycle progesterone has monthly spikes up to 1200% of the baseline ², but everyone else over 16 will have a serum level between 0.3-3nmol/L ³.

So what does it do?

As with everything we’re still discovering everything, but these are some of the functions that have been shown in research several times.

Progesterone is involved in breast tissue maturation⁴. While progesterone does not have any effect on initial breast growth, once Tanner stage IV is reached progesterone causes lobuloalveolar development, filling out the breast, increasing the size of the areola, and preparing the tissue for milk production. So progesterone does have a function in breast growth.

Heart health is also impacted, particularly the QT interval. Oestrogens increase the QT interval whereas androgens and progesterone shorten it⁵. This isn’t a significant thing for most people, but it’s definitely an effect. Additionally 100mg-300mg has been shown to lower blood pressure⁶.

Sleep is another area that’s affected, with progesterone being shown to reduce stress hormone levels, increase deep sleep, and prevent sleep disruptions ². Again not a huge thing clinically, but it’s not “nothing”.

Risks?

The form of progesterone generally considered the best among the transgender community is micronised bio-identical progesterone. This is identical to natural human progesterone that has been processed to make the powder as fine as possible and then suspended in a food oil (generally sunflower from what I’ve read). As this is identical to natural progesterone it has no known negative side effects in regular oral doses⁷, and only site-related side effects in other forms (eg injection site pain).

A lot of literature mentions an increase in drowsiness or memory function, but the paper that seems to be the source mentions this is with 300-1200mg per day, with symptoms increasing with dose⁶. The paper seems to suggest that this is due to the metabolism of progesterone to 5𝛼- and 5𝛽- pregnanolone in the liver, which is due to the administration route. Oral administration always results in a high level of liver metabolism.

So for bioidentical micronised progesterone the risks seem minimal, even if there are no effects.

Progestins then?

Progestins are synthetic drugs that mimic progesterone. They are used because progestins can be designed to avoid liver metabolism, which supposedly reduces the risk of side-effects and greatly reduces the dose required. The most referenced one in HRT is medroxyprogesterone acetate (most common brand is depro-provera), but there’s another one that’s much more common in New Zealand.

Cyproterone Acetate

Cyproterone Acetate, or CPA, is the most common anti-androgen prescribed for feminising hormone therapy in New Zealand. CPA is a progestogen and is said to be 1000 times more potent than progesterone itself. So if you’re on 12.5mg/day of cyproterone acetate it will be stronger than 100mg of progesterone daily in terms of progesterone receptor activation.

No evidence of effect?

This is technically correct. There have been very few studies on the effects of progestogens in transfeminine hormone therapy. Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study uses a synthetic progestogen and was inconclusive, and the only clinical article I have found that takes a deeper look recommends using progesterone as it’s important to cis women (Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen ⁸).

So?

Unfortunately all this evidence hasn’t been enough to sway clinicians from their desire to deny treatment which, while it may have limited effects, is demonstrably safe. Personally I have found it helpful for my mental health and sleep quality at the very least.

I also really wish it wasn’t necessary to become an amateur endocrinologist to know whether doctors are telling us the truth about the medication we’re prescribed, but here we are.

Also Jerilynn C Prior has done some some amazing work on the way progesterone has been (and continues to be) ignored as an essential part of woman’s health. I wish I could talk to her and get more background, but alas I’m not a real endocrinologist.

Every so often articles pop up claiming that transgender hormone therapy is “experimental” or “unapproved”. HRT has been used by transgender people since the 1950s, so it definitely isn’t experimental though like all medicine it’s always improving. However it is “unapproved”, or, as it’s more commonly known, off-label.

This isn’t strange though, many medicines are used off-label. One that I’ve had before is bupropion which comes in multiple brands with different approvals. The only approved brand of bupropion in New Zealand is Zyban, and its approval is only for an aid to quit smoking in 150mg doses. Overseas the Wellbutrin XL brand, which has the same active ingredient and same doses as Zyban, is approved as an anti-depressant. Because Wellbutrin isn’t approved in NZ doctors just prescribe Zyban, this is off-label but backed by overseas approvals.

Bupropion is also used for ADHD. While this is backed by emerging research it isn’t approved for ADHD treatment anywhere, so all ADHD treatment with Zyban is off-label.

Using approved medicines for off-label uses is permitted under NZ law at the discretion of doctors, the safe treatment levels and side effects are established so the risk is minimal. Unlike completely unapproved medicines there’s no special requirement to record these prescriptions.

So why don’t manufacturers apply for these uses? Because it costs money. To get approval in NZ you need a sponsor in the country - normally the importer - and have to submit all the documentation to Medsafe, pay them, and wait. While overseas approvals do help the process they aren’t automatically recognised. So if you make Wellbutrin are you going to go through this, knowing that Pharmac won’t fund it because they already fund one sort of bupropion? Nope. If you make Zyban are you going to pay for the update to the approved indications and submit all the documentation given that doctors can already prescribe? Unlikely.

The only time the Medsafe fee is worth paying is for medicines advertised direct to consumer, as only approved indications can be advertised. This also applies for advertisements sent to clinicians, but there are ways to avoid that and clinicians do read published studies so are likely to be aware of changes.

So where does this leave HRT? The market is small, so the expensive studies required are both hard to justify and hard to find participants for, the medicines are already approved and available, and safe levels are established in literature (and given the hormones are bio-identical easy to validate). This means no manufacturer is going to go to the effort of getting their medicine approved for transgender HRT - menopausal HRT is the vast majority of its use.

Disclaimer: I’m not a medical professional, but I’ve got familiar with the terms from them. I hope this will help others understand what medical professionals mean.

I’m going to cover two things in this post, what informed consent means in the broader medical context and what it means to transgender healthcare.

What is informed consent?

Informed consent is the underlying basis of all modern non-emergency medicine. In order to provide any medical treatment the patient must consent to the treatment and the patient must be provided the risks, benefits, and method of the treatment, and the clinician must be sure the patient understands the information. This is one of those things that seems pretty obvious, but historically has been far from the truth.

So whenever you see a doctor and they prescribe any form of treatment there’s a mental checklist they do:

• Has the patient been informed about this treatment, either now or in the past?
• Does the patient understand this information?
• Has the patient consented?

Of course humans are human and this isn’t done perfectly every time, so it’s repeated. This is why (good) pharmacists will check you understand the medicine as well, and surgeons re-check your understanding before they start the procedure.

There are two factors that aren’t quite obvious here. One is that for things like medicine you can opt not to take them, so full details don’t have to be provided in the appointment and instead an information sheet can be given to you. The other is that to understand if the patient understands the risks the clinician themselves must understand them, this is why sometimes you’ll be referred to a specialist to confirm a prescription even though it could have been done by the first clinician.

Informed consent in transgender healthcare

Now this is slightly different, it relates to the historical pathologisation of transgender people. This means requiring a formal diagnosis of gender dysphoria by a psychiatrist prior to commencing HRT, which may require several sessions withe the psychiatrist and historically the awful practice of “lived experience” - living full-time as your true gender prior to any form of medical treatment. Thankfully most areas in NZ don’t require psychiatric evaluation (looking at you Otago and Nelson) and lived experience is consigned to the history books.

So informed consent means two things here, first the medical basis of treatment, and secondly your ability to request gender-affirming treatment without any formal diagnosis - in fact being transgender is not considered a medical condition at all.

Of course the prescriber still needs to be sure you fully understand the effects and risks of HRT. This may mean requiring a psychiatric evaluation to ensure your understanding (but not for a diagnosis), or referral to a specialist gender centre. Both WPATH and PATHA are clear that withholding HRT is not a neutral stance and is likely to lead to worsening of mental health, but unfortunately this message hasn’t got through to everyone.

To be clear this is also true of any other medical treatment, but GPs tend to be much more risk-averse with conditions they haven’t encountered a lot. There are also some areas in NZ with particularly backwards health authorities who insist on psychiatric evaluations and other gatekeeping, even though this is against the national guidelines and the practitioners might be comfortable with evaluating by themselves..

Cool, and?

And this is the cause of a lot of confusion. Informed consent means one thing to medical professionals and a similar but subtly different thing to the transgender community. While clinicians used informed consent to mean validating the patient’s understanding of the treatment, we use informed consent to mean removing the old barriers to treatment, so get very frustrated when these are still present.

Ideally patient-driven therapy would be more accepted, where patients can set their own hormone targets and clinicians monitor for unsafe dose levels or negative health effects. Unfortunately this is a significant step for healthcare providers and unlikely to happen, even though it would get people off DIY HRT on to safer methods. This wouldn’t be universal, a lot of people feel safer or just prefer having doctors set the treatment plan.

Lastly the lack of an actual diagnosis does put transgender healthcare in a slightly weird spot; it’s not considered a medical condition, but we still need medication. This does have some implications that I’ll explore in a later post.

I’ve now heard from multiple people that their doctors or endocrinologists have told them laboratory tests for oestrogen levels are either inaccurate or cannot detect exogenous oestrogen, so there’s either no reason to test or no reason to take action based on test results. This always seems to be used to deny increase in hormone doses, but for decreases the blood levels are always trusted. Interesting that…

What are we measuring anyway?

Oestrogen isn’t one substance, but the oestrogens we’re interested in are oestrone (E1) and oestradiol (E2). In general E2 is the predominant oestrogen in adults and the most common form for HRT. In New Zealand we only have tests for oestradiol available, which lines up nicely with what we want to measure.

What is HRT oestrogen?

All HRT oestrogen is oestradiol. There are two common forms of oestradiol in New Zealand, oestradiol valerate - the ester of valeric acid¹ and oestrdiol - and oestradiol hemihydrate which is pure oestradiol with extra water in the crystalline structure (yes I’m vastly simplifying this) ².

Oestradiol valerate is a prodrug - it is not biologically active, but it is metabolised in to oestradiol and valeric acid in the body ³. There’s no need to measure oestradiol valerate as it’s not active, only the oestradiol it’s metabolised in to.

Oestradiol hemihydrate doesn’t need any metabolism, it’s already oestradiol. The extra water is broken away as the oestradiol hemihydrate dissolves in to your bloodstream.

In both cases the biologically active component is identical to oestradiol produced in your body, so would be detected by any system that detects oestradiol.

How do we measure it?

For the full details you’ll have to read Challenges to the Measurement of Estradiol: An Endocrine Society Position Statement ⁴, but here’s a TLDR. The best method is a complicated system of isotope dilution/gas chromatography coupled with mass spectrometry but that’s far too slow for practical use. Most modern systems use immunoassays.

What’s an immunoassay?

Chances are you’ve used one! The general concept is the same as the COVID-19 self-test I’m sure many of us have used, except with far tighter tolerances so actual numbers can be derived. The basic principal is an antibody is developed that attaches to the desired molecule - oestradiol in this case - and the number of matches is counted. This is done by introducing a second competitive molecule that attaches to the same antibodies but fluoresces, then you can measure the light given off to determine the amount of antibodies that weren’t bound to the oestradiol. If you know how many antibodies you included in the first place and the amount of light each molecule will emit you can calculate the total oestradiol there must have been! Simple!

Simple?

Not really. There’s a bunch of consideration here. The affinity of the antibodies for oestradiol, the sensitivity of the photosensor, the variability of fluorescence, how consistent the reagents are in antibody count, the potential for things other then oestradiol to also bind to the antibody, and a whole bunch of other things I don’t understand.

Fortunately modern laboratories can quantify these problems and produce error ranges for their assays. However there are limits to the detection, and different assays are often not comparable - that is if you use a single assay type you can compare the numbers, but if your lab changes their system then the numbers can’t be compared.

What assays does NZ use?

It’s hard to tell, labs don’t always disclose this which is quite annoying.

From what I’ve been able to find New Zealand’s labs have standardised on Roche assays ⁵. I found the Roche technical documentation on their oestradiol tests, and while I can’t be certain this is what the labs use it lines up with their stated performance and machines.

This assay can detect down to 18.4pmol/L, but can only accurately quantify levels over 91.8pmol/L. Even then their data tables show the measurements are only accurate to ±7% at 100pmol/L, but this improve to ±3% at 200pmol/L and ±2% by 500pmol/L. So a constant level may fluctuate slightly over multiple readings, but it’s good enough to establish trends over multiple tests. A single test with an unexpected level should be repeated though as there is a remote possibility for a bad read (However depending on the records the lab has about your gender they may have already done this). Additionally the amount of oestradiol in your blood will vary based on activity, time of day, diet, all sorts, even on a fairly constant dose system like patches.

So can we measure HRT oestradiol, and accurately?

Yes, we can detect HRT oestradiol. It’s identical to regular human oestradiol.

Yes, the tests used in New Zealand are accurate for levels over 100pmol/L. There will be variance because the tests aren’t exact, but they are accurate enough to establish trends - if your oestadiol levels are going up the results will trend upwards, or vice versa. Or be around the same values.

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!

Why?

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 $350\text{pmol}/\text{L}$. NZ standards say $700\text{pmol}/\text{L}$ 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 $272.388\text{g}/\text{mol}$³, and the typical adult has around 5 litres of blood, for a total of 1,750 picomoles of estradiol, or $1.75\times {10}^{-9}$ moles. Doing the math gives $4.7668\times {10}^{-7}\text{g}$, or $476.68\text{nanograms}$ of estradiol total. Wikipedia says the metabolic clearance rate of estradiol is around 1200L/day, and given the previous calculation this means that $\frac{1200}{5}\times 476.68\text{ng}=114,403\text{nanograms}$ of estradiol, or $114.4\text{µg}$, per day would be needed to balance out the metabolic clearance rate.

Actually that would leave you with zero oestrogen, so lets make that $114.8\text{µg}$ 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. $450\times {10}^{-12}\text{mol}/\text{L}\times 272.388\text{g}/\text{mole}\times 1200\text{L}/\text{day}$. 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.

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!