Those familiar with Betteridge’s law of headlines will be able to quickly answer this, but commonly held wisdom says that estrogen - whether endogenous, as part of any hormone replacement therapy, or as part of hormonal contraception, increases your risk of breast cancer.
This is distinct from the misinformation that’s commonly spouted with gender-affirming oestrogen HRT by comparing the risks of cancer with HRT against that of cis men, who notably do not have significant amounts of breast tissue to develop cancer in (it does happen, it’s just far less common).
These beliefs are used to dissuade people from getting or continuing menopausal HRT and also to restrict people on gender-affirming oestrogen therapy from obtaining appropriate levels of medication. So let’s dig in.
What’s commonly believed
Breast cancer is either the most common invasive cancer or the second most common after lung cancer, and as such it has had a lot of research. This research has firmly established that the majority of breast cancers are hormone-dependant, that is they require a hormone to grow, and nearly 80% of all breast cancers are oestrogen-receptor positive (ER+) and oestrogen is required for the cancer to grow1. The research is backed up in practice by using anti-oestrogen and oestrogen receptor modulation drugs to successfully halt tumour growth prior to surgery.
This appears to have lead to the oft-repeated assertion that exposure to increased levels of oestrogens increases your risk of breast cancer, which is associated with use of combined hormonal contraceptives and hormone replacement therapy whether gender affirming or menopausal.
However when looking for the research backing this up I found the statement repeated often but no papers actually showing this. There were some papers focussing on menopausal HRT that showed an increasing risk of breast cancer with duration of HRT compared to a non-HRT-using control group, but the association was very tenuous.
Then while researching this after hearing about another person denied an increase in HRT due to this supposed cancer connction I found a recent paper on this subject.
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 multiplesources saying it should be up to the patient I’d like to know, and I’m sure a lot of others would as well.
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.
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.
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.
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.
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!
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.