When talking about progesterone doctors often refer to the lack of clinical evidence to support the use of progesterone, so let’s look at the evidence behind the target levels of oestrogen cited in many feminising hormone therapy guidelines. The latest PATHA guidelines say to keep below 750pmol/L but do not specify further.

Fortunately a group of researchers have recently published a systematic review of this, so I can cite their work instead of trying to obtain copies of articles!

The paper titled Estradiol Concentrations for Adequate Gender-Affirming Feminizing Therapy: A Systematic Review¹ identified papers with appropriate data to review estradiol levels for sufficiency, insufficiency, and toxicity for bio-identical estradiol. In plain English they were looking for the levels at which you get enough oestrogen, too much oestrogen, and not enough oestrogen for feminising hormone therapy. Additionally they excluded studies that looked at non-bioidentical oestrogens such as ethinyl estradiol or conjugated equine oestrogens as those have very different biological side-effects to human 17β-oestradiol.

I don’t like suspense, so here’s the conclusion:

There is no evidence to support either a lower or upper limit of estradiol during feminising hormone therapy.

Target levels

I’m going to pick some quotes from the paper, but it’s not very long so read it yourself! I’ve converted the US picograms per millilitre in to SI picomols per litre - the conversion factor is 3.6712.

Estradiol concentrations in premenopausal cisgender women vary widely through the menstrual cycle, with peak concentrations exceeding 500 pg/mL [1800pmol/L] and across cycle average concentrations of up to 300 pg/mL [1100pmol/L]. A range of 100–200 pg/mL [367-734pmol/L] is not representative of healthy adult cisgender women and, as such, does not correspond to any existing guidelines for perimenopausal or menopausal HT.

and

Even still, a recent publication called for lowering the injectable dose of estradiol to avoid transient experiences of higher estradiol concentrations in transgender women and to improve the chances of achieving concentrations within the guideline range. However, such studies do not present a rationale as to why the guideline range of 100–200 pg/mL was prescribed and do not provide references that support its therapeutic use.

So there’s no evidence to support the range, but clinicians are treating it as if there is.

Toxicity and side effects

A major reason for setting an upper limit of any medication is the side effects, as dose increases so do side effects and the impact of adverse side effects may limit the therapeutic use.

The paper analysed all the reports to identify a dose-dependant correlation of estradiol with negative side effects and found… nothing. The data included liver enzyme levels, liver damage, gallstones, venous thromboembolism, cardiovascular disease, and stroke.

No relationship between estradiol concentration and clinical toxicity was observed for any of the potential pathologies.

Prolactin levels were observed as increased in some studies, but these attributed it to the use of cyproterone acetate rather than estradiol.

Conclusions

The only conclusion the analysis could draw is that there is no evidence to back up the guidelines. Of course this means that more research is needed, but as they point out

There were no additional risks of gender-affirming feminizing HT associated with estradiol concentrations outside the 100–200 pg/mL guidance range.

Which means the current evidence shows that the upper limit on serum estradiol is not based on any risk of side-effects.

References

1. Winston-McPherson, Gabrielle N. and Thomas, Tiffany A. and Krasowski, Matthew D. and Ahmed, Sofia B. and Cirrincione, Lauren R. and Katzman, Brooke M. and Pierre, Christina C. and Rytz, Chantal L. and Turino Miranda, Keila and Goldstein, Zil and Greene, Dina N.. Estradiol Concentrations for Adequate Gender-Affirming Feminizing Therapy: A Systematic Review. LGBT Health. 2025;12:477-489. doi:10.1089/lgbt.2024.0407. PMID: 40552461.¹