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.
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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!
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”.
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 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, 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).
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.
Christine L. Clarke, Robert L. Sutherland, Progestin Regulation of Cellular Proliferation, Endocrine Reviews, Volume 11, Issue 2, 1 May 1990, Pages 266–301, DOI: 10.1210/edrv-11-2-266
Tara Sedlak, Chrisandra Shufelt, Carlos Iribarren, and C. Noel Bairey Merz. Sex Hormones and the QT Interval: A Review. Journal of Women’s Health. Sep 2012.933-941. DOI: 10.1089/jwh.2011.3444
Goletiani, N. V., Keith, D. R., & Gorsky, S. J. (2007). Progesterone: Review of safety for clinical studies. Experimental and Clinical Psychopharmacology, 15(5), 427–444. doi:10.1037/1064-12184.108.40.2067
Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(sup1), 3–63. doi:10.1080/13697130500148875
Gräf KJ, Brotherton J, Neumann F (1974). “Clinical Uses of Antiandrogens”. Androgens II and Antiandrogens / Androgene II und Antiandrogene. pp. 485–542. doi:10.1007/978-3-642-80859-3_7
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.
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.
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!
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.
Valeric acid is named after the plant valerian, where it’s found in the roots. Valerian root is often used as a herbal sedative or sleep aid.
William Rosner, Susan E. Hankinson, Patrick M. Sluss, Hubert W. Vesper, Margaret E. Wierman, Challenges to the Measurement of Estradiol: An Endocrine Society Position Statement, The Journal of Clinical Endocrinology & Metabolism, Volume 98, Issue 4, 1 April 2013, Pages 1376–1387, https://doi.org/10.1210/jc.2012-3780
Medsafe is New Zealand’s medication regulatory authority. Except in a few cases all the medications on sale in New Zealand, and certainly any you see on shelves or advertised, have Medsafe approval.
This is a very important role - Medsafe ensures medicines meet the quality and efficacy the manufacturers claim, is safe to use in the way the manufacturer has specified, has appropriate guidance for patients and prescribers, and has a secure distribution network.
So why is this a problem?
Medsafe is industry funded. That is, to sell a medication in New Zealand you first have to pay Medsafe for the privilege of approval, supply all the documentation that Medsafe require, and wait for Medsafe to process your application.
This process can cost from NZ$10,000 to over $100,000 depending on the category of medicine. Medsafe do not recognise any overseas approvals.
The end result is unless a manufacturer or importer can justify the cost of Medsafe approval they won’t apply for it. Medications that are perfectly usable are unavailable in New Zealand because the cost is too high. This can be seen with the current oestrogen patch shortage - two brands which are just as effective as the only approved one are being prescribed under Section 29 of the Medicines Act, but they’re unapproved because there isn’t the demand to pay for Medsafe approval.
What about Section 29?
Section 29 allows for registered doctors - not nurse practitioners, dentists, or other medical practitioners who could prescribe an approved medicine - to prescribe medicines without Medsafe approval.
However, when something is prescribed under S29 the name of the patient, prescriber, supplier, and the medicine have to be sent to the supplier, who must store this information and forward on information about the medicine supplied (but not patient details) to Medsafe.
This means any supplier of S29 medicines has to maintain a database of what they’ve supplied and who they sent it to. Which isn’t great for things like hormones…
Additionally doctors seem wary of prescribing under S29 unless they’re really familiar with the medication. I don’t know why.
How could we address this?
Make Medsafe work for the health of New Zealanders, either by funding its work or by recognising overseas authorities. We collaborate with Australia on food regulations, why not medication?
Of course these things take far too long. It was recommended that the maximum length for a prescription be increased from three months to six, and from one to three for controlled drugs. Only the latter has actually happened. At least they’ve dropped the $5 kick-in-the-teeth when you’re sick charge.
With the shortage of Estradot I’ve seen quite a few people wondering what all the different ways medication is described in New Zealand actually mean. What is an unapproved medication? What is a special authority? Hopefully I’ll answer that!
This isn’t an exhaustive list, just the ones you’re likely to see.
Funding (and Pharmac)
Lets start with the funding because it’s the easiest to understand, this comes from Pharmac - the buyer of most medication prescribed in New Zealand. There are four common funding states - unfunded, partially funded, fully funded, and special authority.
I’m only discussing the community schedule which you can handily search online - just put a medication brand or generic name in the search box to find out the funding status.
Pharmac have a set budget so fund the medications they believe will have the most impact for the amount they cost.
This is the easiest one - unfunded medications do not have any funding from Pharmac, you’ll pay the full market price.
Some less-common medications attract partial funding, for example some preparations of povidone-iodine are partially funded, so you’ll pay the market price less the Pharmac funding. For example Betadine Skin Prep attracts a $1.63 subsidy but the remainder has to be paid by the patient.
This is the most common state for medications prescribed in New Zealand. These are the ones that (from July 2023) are free to collect from the pharmacy as Pharmac pays the full cost of the medicine. However…
Sometimes there are funding restrictions, generally due to cost of medicine or likelihood of wastage. A great example is the Estradot oestradiol patch. These are funded for a maximum of two per week, or 8 per 28 days, so if you need 200mcg at a time you have to pick up the second pack yourself. Fortunately this is only around $18 per 8 patch box.
These restrictions are only on quantity supplied - either minimum, maximum, or only in whole packs.
For both partially and fully funded medications Pharmac will fund any use, they just pay the pharmacies. However there’s a case where they do care about the reason, so we have
Special Authority funding is for medications where Pharmac only fund for specific conditions or cases. These require a form to be filed with the pharmacy and Pharmac to get the subsidy - which may be full or partial - and a renewal of authority on a schedule. An example that comes to mind is the ADHD medication Concerta. Concerta is only available for patients who have some reason to not take the immediate-release versions, either addiction liability, lack of response, or an allergy to the ingredients (Ritalin IR contains wheat!).
Special Authority doesn’t prevent prescription, only Pharmac subsidy. The Utrogestan brand of micronised progesterone used to be special authority for funding (only specific cases of menopausal HRT) but could be freely prescribed, as long as patients would pay the full price (around $25 for 28 days if I recall).
So that’s funding. However funding isn’t the full picture, what about approved and unapproved? Section 29? These are nothing to do with Pharmac, so now we introduce the other half of the equation, Medsafe.
Approval (and Medsafe)
Medsafe are the regulator of medicines in New Zealand. Most medicines have MedSafe approval and approved indications, but practitioners can prescribe unapproved medicines. So lets look at these
Medsafe are an industry-funded government department, this means that if you want an approved medicine in New Zealand you have to pay the Medsafe fee. It costs between $50,000 and $110,000 to get a medication approved, plus the costs of getting the required data in to the format Medsafe need. This means that manufacturer or importer won’t apply for approval for medication unless they think they’ll be able to make their money back.
As an aside, Medsafe approval only covers conditions specified in the application for approval. However nothing stops an approved medication being prescribed for an unapproved indication - also known as “off label” - such as bupropion which is only approved as an aid to smoking cessation but is also used as an antidepressant.
Unapproved medications and Section 29 of the Medicines Act 1981
Because approval is industry-driven when they wrote the Medicines Act they realised that sometimes an unapproved medicine will be needed, for example with rare conditions or new medicines before approval is obtained. So Section 29 allows any doctor (specifically a doctor, not a nurse practitioner or pharmacist) to prescribe any unapproved medicine. However this must be reported to Medsafe by the supplier, Medsafe use this to monitor the use of unapproved medicines and direct practitioners to use approved ones where possible.
Section 29 prescriptions are for a named patient and a specific brand, so pharmacies can only supply the exact brand and quantity asked for (or an approved generic substitute, but in general that wouldn’t happen for an S29 prescription).
Additionally Section 25 allows a practitioner or pharmacist to import a medicine not otherwise available in New Zealand.
How this relates to Estradot
Estradot - and oestradiol patches in general - are in short supply worldwide. Estradot is the only patch that is approved for sale by Medsafe, and also fully funded (*with restriction to one pack per month 😞) by Pharmac.
Due to the shortage Pharmac have sourced alternate patches, Estraderm MX and Oestradiol TDP Mylan, but these are unapproved. This means there’s an odd situation where a doctor has to prescribe Estraderm MX under S29, but these are still fully funded because approval and funding aren’t linked. Pharmacies can legally substitute approved Estradot for unapproved Estraderm MX, but not the other way around.
I hope this makes things a little more clear…
An aside - controlled drugs
Completely unrelated to the above, controlled drugs are specified by the Misuse of Drugs Act 1975. There is no prohibition for prescribing controlled drugs - and in fact all classes of controlled drugs are available if hospital only use is considered. Medsafe and Pharmac do not consider the controlled status, only the medical utility. Controlled drugs can be prescribed under S29 if the prescriber can justify the use - this is how medicinal cannabis is currently managed.