I’ve recently been forwarded a document that the Victoria University of Wellington’s Mauri Ora Student Health clinic has been using to blanket deny their patients progesterone, even going as far as to forcibly discontinue the prescription from people already prescribed it.

I normally avoid doing a critique of a specific practice because there are many factors that go in to the decision to prescribe, but I was shocked that this practice would just invalidate a standing prescription without any evidence of harm. Not prescribing because of a lack of knowledge of the correct process or side effects is one thing - a doctor cannot provide informed consent if they themselves are not informed - but to remove an existing medication because they don’t like it is quite another. Imagine if a doctor refused to continue a contraceptive prescription because they had a personal belief against it? In certain circumstances doctors can refuse to prescribe due to personal beliefs, in which case they are required to refer you to someone who will.

So lets pick apart their reasoning to see if there’s anything behind it, because if progesterone is dangerous despite multiple sources saying it should be up to the patient I’d like to know, and I’m sure a lot of others would as well.

I’ll link the full text below, OCR was used on photos sent to me to extract the text.

So let us look at their reasoning, as presented in their information sheet. I’ll use their sections as well.

Evidence

Currently, no medical evidence exists that progesterone provides any additional feminisation benefits for TGNB people

This, as I’ve previously discussed is technically correct. There is no medical evidence that progesterone provides any benefits. There is also no medical evidence that progesterone does not provide any benefits. There are two studies on the effect of progesterone in trans women I know of, both are inconclusive due to a small cohort and short duration, though there is a large scale study in the Netherlands which I think has finished so will hopefully publish soon.

However they explain this more, so lets go in to their reasoning

No high quality evidence that progesterone increases breast tissue in TGNB people.

Again there is no evidence because nobody has looked. The study I mentioned above is looking at this.

Evidence shows that most trans feminine people are able to achieve size AA- or A-cup breasts over sustained treatment with oestrogen and androgen blockage, with maximum effects achieved over 3-5 years. After this point and during treatment, complementary interventions are available […]

Read: “Because we refuse to prescribe proper levels of hormones our patients never achieve real breast development so we recommend implants, padded bras, and breast forms”.

Ok I was a tad angry there.

There is nothing to suggest that when given appropriate levels of hormone therapy trans women will not achieve the same breast development as cis women.

Anecdotally some TGNB people feel progesterone is helpful for mood or sleep. There is no evidence that progesterone plays any role in the natural sleep cycle. …

Saying progesterone does not affect sleep is simply¹ not² true³. There are many studies showing that micronised progesterone has a positive impact on sleep, and is part of the natural sleep cycle. The impact on mood is anecdotal, though high levels of progesterone correlate with a decrease in mood during the menstrual cycle.

… A deterioration in mental wellbeing is a recognised side effect of most forms of progesterone treatment, and at present there is no good quality evidence to suggest that progesterone improves mood in any way.

Actually true for once. It’s not just progesterone though, it’s all progestins that are associated with negative mood impact. Progestins are a group of hormones including progesterone, several metabolites of progesterone, and many synthetic progestin-analogs that are used in medicines.

The main anti-androgen used in New Zealand is cyproterone acetate - a progestin around 1000 times more effective at binding to progesterone receptors than progesterone itself⁴. Rejecting progesterone for this while prescribing cyproterone acetate is rather disingenuous.

Ok. Next section

Risks and negative effects

In all shared decision-making in medicine, we must balance risks and benefits for every patient.

Absolutely true. However the risks should be balanced against the patient’s ability to make informed consent for the level of risk they’re willing to tolerate, not what someone else thinks they should tolerate.

Blood clots

[…] Several factors affect your risk of clots (such as family history, smoking, recent surgery). We know that taking oestrogen (excluding ostrogen patches) increases the risk of blood clots, […]

Ok stop here. All oestrogen at GAHT levels including patches raises your risk of blood clots. Patches aren’t a get-out-of-jail free card. Again I’ve previously looked at the risk of blood clots in HRT, and the risk doesn’t increase with dose until you get to extremely high doses. There has only been one documented case of blood clots in a person receiving bio-identical gender-affirming hormones who did not have additional risk factors (smoking, diabetes, surgery, HIV etc).

The risk for trans women using hormones is about double that of a cis woman who isn’t using hormonal birth control, but that level is so low it’s not worth risking someone’s short term mental health over a very unlikely long term risk. The risk of blood clots from hormonal birth control is much higher, yet there’s no restriction on their prescription.

Newer forms of progesterone such as utrogestan have a lower risk of blood clots than older forms; but further studies are needed.

Utrogestan - micronised bio-identical progesterone - was introduced to the market by Besins Healthcare in 1980. That’s 45 years ago as I write this. There have been plenty of studies on it and they have shown that there is no blood clot risk from utrogestan⁵.

Older forms such as medroxyprogesterone acetate are synthetic progestins, utrogestan is identical to natural human progesterone. If natural human progesterone or its metabolites caused a significant increase in blood clots it would be a problem for all women.

Cancer

Animal studies have shown an association between progesterone and breast cancer. Progesterone use in older cis women beyond the menopause also appears to be associated with an increase in breast cancer risk. All TGNB people taking oestrogen with breast tissue development are already at increased risk for developing breast cancer.

OK. Lets pick apart that last point, because there’s a large study following over 2000 trans women and 1000 trans men in the Netherlands⁶ a great meta-analysis paper⁷ on this. A meta-analysis is one that looks at several existing studies to make what is effectively one larger study.

So do trans women have a higher breast cancer risk? Well yes, but also no.

Both studies say trans women have a significantly higher - the dutch study says 46 times higher - risk of breast cancer than cis men. But what about against cis woman who have a much higher rate of developing breast cancer than cis men? Both studies again agree, trans women have a lower risk of breast cancer than cis women. The Dutch study that looked at trans women with a median of 18 years on HRT, and a max of 37 years, but they controlled for the time since puberty for cis people and time since starting HRT for trans people.

The studies don’t lie - trans women do not have a higher risk of breast cancer than cis women. The risk compared to cis men is not relevant as cis women have a far higher rate of breast cancer.

• In cisgender women utrogestan does not seem to increase breast cancer risk in the first 5 years of use, but there is some increased risk beyond this.
• There are no data regarding breast cancer risk in TGNB people on progesterone.

Actually true for once, backed by a study⁸. However that study also states:

women should also be counseled that the possible increased breast cancer risk with combined MHT is small (<1 per 1000 women per year of use) and lower than the increased risks associated with common lifestyle factors such as reduced physical activity, obesity and alcohol consumption

So again this is a very small additional risk for a population who already have a lower risk of cancer than cis women.

Other risks

Progesterone use in cisgender women is associated with:

• Low mood (depression)
• Weight gain
• Low libido (low sex drive)
• Fatigue

These are associated with progestins, as mentioned cyperoterone acetate is also one. These are also symptoms that are experienced by some women taking progestins as part of hormonal contraception and are normally managed symptomatically.

As with any medication negative side effects have to be part of the informed consent discussion, and if they appear this needs to be managed symptomatically. There’s no issue with recommending discontinuation of progesterone due to side effects, but the presence of potential negative side effects is not a reason to refuse to prescribe. If that was the norm then no medicines would ever be used.

The rest of this “information” sheet goes in to the effect of progesterone on cis women. I’ve picked the most relevant points

Progesterone in cisgender women

During a cis female puberty, progesterone is involved in the development of breast ducts, which are needed for future breastfeeding, but it does not appear have a role in breast volume/size.

This is saying “Progesterone is important for breast function, but trans women will never need functioning breasts so we don’t care.”

There’s no physiological difference in breast tissue no matter how you start growing them, so why would you think a process that’s important for development in cisgender women is not important for transgender women?

When doctors induce is puberty when this has not commenced naturally, we avoid introducing progesterone until breast development is complete, as earlier use appears to blunt breast growth.

This is true, and a good argument for not introducing progesterone at the start of HRT. However it can’t be used as an argument for never introducing progesterone as it’s clearly important.

Progesterone levels are low throughout most of the menstrual cycle in cis women, and only rise transiently after ovulation.

Progesterone levels rise for approximately two weeks of the cycle from around the same level as cis men to 4-10 times that. So for half the time cis women have a significant amount of progesterone.

I haven’t looked in to the effect of testosterone suppression on progesterone production. I should, because it would be interesting to know if using a synthetic progestin like cyproterone acetate reduces the normal production of progesterone. While cyproterone acetate works like progesterone it doesn’t produce the normal range of metabolites such as allopregnanolone, which are known to have different functions.

Contraception […]

Contraception uses synthetic progestins. The side effects are well known and don’t prevent their use. The side effects are discussed as part of the informed consent process.

Menopause

Menopause is a clear set of symptoms to be treated and the level of medication can be compared to the symptoms. You can’t compare the effects of GAHT to the symptoms because the treatment has to last a lifetime.

Conclusion

We have a duty of care and professional practice to do no harm and to practice evidence-based medicine.

As has been outlined in many studies on gender-affirming treatment, the decision to take no action is not a neutral stance. Refusing to prescribe because the medication has a small chance of causing harm in the future is trading the patient’s possible future physical health against their very real short term mental health. Doctors should work with their patients and be able to explain the risks and lack of evidence of benefits to their patients. The only proven risks of progesterone are the same as hormonal contraceptives, and these are freely prescribed.

My conclusion

This so-called “information sheet” has many inaccuracies and overplays risks based on inaccurate comparisons to avoid prescribing a medication that has very few negative side effects.

The problem with the need for doctors to prescribe gender-affirming hormone therapy is they often treat it like any other medication. They want it to cure something, and with any medication you use the smallest amount needed to cure the symptoms. However being transgender cannot be cured or treated solely on a physical symptom basis. While I don’t believe that GAHT should be unregulated, I do think clinicians need to work with their patients to find a regime that they feel physically and mentally well on, and the current guidelines are far too conservative.

The only model we have for appropriate hormone levels is that of cis women, and the range is far wider than the current New Zealand GAHT guidelines acknowledge.

Citations

The problem with having to get a doctor to prescribe gender-affirming hormone therapy is that doctors are trained to treat diseases. When you’re treating a disease you have a clearly defined goal - curing the disease, or minimising the suffering if it cannot be cured. This also extends to the scientific studies used to formulate treatment options, there is a clear and measurable definition of success. This is critical for normal patient care, doctors want to minimise the harm caused - and lets be clear, all medicines are harmful, just less harmful than what they’re treating - while maximising the effectiveness of the treatment.

This doesn’t work for gender-affirming care though. The effects you get from hormones depend a lot on your genetics and we don’t know enough about those to determine if a treatment is fully effective. In terms of M-F transition, we can’t establish if a certain breast size is the one genetically encoded, or if it has been restricted due to a lack of hormones. For those going F-M, is your voice fully deepened or has it stopped because of insufficient testosterone? Does the hormone level actually matter to either or is there just a threshold? We cannot design a study for this, especially given it would have to run for over 5 years to fully capture all the changes.

All of the uncertainty leads to doctors missing out on one half of the risk calculus - if you can’t tell what the target is you’re stuck with minimising the overall risk rather than balancing it against the effectiveness of treatment.

Now I’ll focus on one of the problems this causes

As always I’m looking at academic papers, so there will be medical language used some of which may be outdated.

Arbitrary medication limits

In the latest edition of the PATHA guidelines for gender affirming care, which is the document used by most doctors in New Zealand, there is this paragraph:

There is currently no evidence to suggest that a dose of ostrogen higher than 200mcg/24 hours via patch or 6mg daily orally is helpful, and, indeed, poor evidence to suggest any strong correlation between ostrogen doses at recommended levels and outcomes at all.

which cites as evidence

Moore E, Wisniewski A, Dobs A. Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects. The Journal of Clinical Endocrinology & Metabolism. 2003;88(8):3467-73.|

Time to get the paper! Here’s the summary of the paper on pubmed, your local library may have access to the journal if you want a copy.

At first glance, this paper suffers from very common issues in the field of transgender healthcare. It’s based on outdated medications and, the time period is unclear, some of the discussion compares to post-menopausal HRT, and it contains unjustified dose-level scaremongering.

Outdated medications

In this study the trans-feminine cohort were predominantly treated with ethinylestradiol or conjugated equine estrogens (CEE). There is one that used bio-identical oestrogen, but this was delivered as an injection for the first year.

These are not the medications we use in New Zealand. Both ethinylestradiol and CEE are no longer used for most GAHT because of the known adverse effects which are not present or greatly reduced when using bio-identical hormones, for example blood clots which aren’t a serious problem with bio-identical oestradiol.

It’s also important to note that non-human oestrogen has a different affinity for the various oestrogen receptors in the body. Two studies ^{1 2} found very different affinities for ethinylestradiol to the human oestrogen receptor, but neither of these had the same balance as human oestrogens do. Does this make a difference in GAHT? We have no way of knowing. CEE has a different binding profile as well.

Additionally most of the reports used cyproterone acetate in doses of 50-100mg per day which is a very high dose of a medication with known dose-dependant side effects, and is also known to be just as effective at much lower doses. Cyproterone acetate is a progestin, and has a very high affinity for progesterone receptors, which are implicated in breast development in animal models.

Study duration

It’s hard to pinpoint the duration of this study as it’s based on reports from multiple worldwide practices. They all seem to have different standards, but it takes several years for transition - puberty takes 8+ years and there’s nothing to indicate gender transition would be different - so studies have to run for a long time to see all the effects.

Comparison to menopausal HRT

This happens a lot in so many studies. Menopausal HRT and GAHT are not comparable in their goals and measures of efficacy. HRT for menopause has clearly defined symptoms so the dose can easily be adjusted to the lowest possible to relieve them, and lets remember that the surge of demand for HRT came after a TV documentary showed how badly treated women with menopause were by doctors, either through ignorance, not updating their knowledge about treatments, or plain dismissal of symptoms as important.

Menopausal HRT is aimed at reducing symptoms from a drop in hormones, not replacing hormones to effect a change. Doses for GAHT will have to be higher, we should be aiming for adult levels of hormones.

Dose level scaremongering

Quotes from the paper

Treatment that exceeded recommended estrogen dosages in M3F transsexual people was reported by eight subjects (45%), and five subjects (28%) reported three or more times the recommended dosage. […] Additionally, despite the hesitancy of providers to distribute injectable hormones to M2F transsexual people, 28% reported their use. In light of the older age of subjects, these high doses and complex regimens were particularly concerning for increased risk of adverse effects.

Doctors are always concerned about the risk of adverse effects, but they rarely seem concerned about the patient’s concern for these risks, or attempt to balance it against the mental distress of gender dysphoria.

All medications carry the risk of adverse effects, it should be up to the patient to determine their risk level.

My conclusions

I don’t think this study provides the evidence for any restriction of dose levels. There are reasons to had a maximum dose level, but this study doesn’t provide them. It reports on medications that we do not use, that have different absorption and biological effects, and seems more interested in commenting about how the doctors are concerned about the levels than the patients’ overall wellbeing.

While I’m not advocating for a hormone free-for-all I do wish that doctors would work with us rather than against us, ensure we know the long and short term risks and allow us to make our own choices.

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.

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!