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.

New research

Of course this research is based on menopausal HRT, since that is by far the biggest use of oestrogen HRT, but if the previous studies could be extrapolated to all HRT then surely this one can.

Originally published on 8th November 2024, and now as free text on pubmed, J Kim and P. N. Munster’s paper Estrogens and breast cancer² goes in to the prior research and draws a very different conclusion.

Oestrogens, no matter the form, have little impact on the risk of developing breast cancer and may actually decrease the long-term risk. One long term study referenced in the paper showed that after oestrogen-only menopausal HRT the risk was reduced by over 20% when monitoring participants for more than 20 years.

Progestins, on the other hand, are strongly linked to the risk of developing breast cancer, based on both menopausal HRT including a progestin and progestin-containing hormonal contraception. The same study as before showed a 28% increase in breast cancer risk.

But what is the actual risk?

The risk of developing breast cancer is often quoted as 10-13% over a lifetime. Research has shown that the risk is higher in more developed countries – though there’s a lot of commentary that this may be due to more screening and better health systems – and that age is the primary risk factor in developed countries with under 20% of cases being in those under 50³.

A presentation abstract by Cutler et al⁴ comparing the estimated post-menopause case count with the actual number of cases reported shows a much lower rate of somewhere between 2-5%, but I can’t find more details on the rest of the presentation.

Even assuming a lifetime risk of 10%, a 20% increase only moves it to 12%. For some this may be a risk they’re wiling to take.

What does this mean for HRT?

This is another case where oestrogen is demonised but the research has disproved it, much like blood clots. Oestrogen HRT may actually reduce the risk of breast cancer.

And again, the progestins are the actual culprit, though for menopausal HRT with an intact uterus progestins are unavoidable due to the increased risk of uterine cancer without them.

In gender-affirming HRT on the other hand this appears to case a very bizarre cognitive dissonance for many doctors. They’ll use these facts to deny prescriptions of bio-identical progesterone to patients, while at the same time being completely willing to prescribe cyproterone acetate.

Cyproterone acetate is a progestin, it’s much more powerful than progesterone itself with reports of it being 1,000 times more potent⁵. Coupled with the lack of first-pass metabolism experienced by cyproterone acetate, the standard dose of 12.5mg per day will result in a far higher progestrogenic effect than an oral dose of 100mg of bio-identical progesterone.

It still boggles my mind how people on oestrogen gender-affirming HRT using bio-identical human hormones, the ones we all require to live and can’t have an adverse reaction to, are considered the risky ones and the synthetic options with known serious side-effects are much easier to to get. It’s not uncommon to hear of doses of 50 to 100mg of cyproterone acetate being prescribed long term, but this dose is only indicated by the manufacturer for short-term treatment of androgen-dependant cancers while awaiting surgery.

Hopefully this research filters down to the people who prescribe, but for now we can educate ourselves.

References