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