The cloud visualization does not represent individual data points; rather, it illustrates the uncertainty inherent in the model itself. Importantly, this visualization underestimates the total uncertainty, as it only captures the uncertainty associated with the population mean, or more accurately the uncertainty in the parameters of the deterministic estradiol curve. It does not account for the full distribution of outcomes across the broader population. This limitation is expected to be addressed in future updates by incorporating a more comprehensive representation of uncertainty, including population variability around the deterministic curve.

Current understanding suggests that the pharmacokinetics of estradiol ester depots is highly variable and influenced by numerous factors that are not well understood or consistently accounted for in existing models of this class of drugs. These factors can lead to significantly divergent outcomes and are often poorly represented, if at all, in current modeling efforts. Key variables include ester concentration, the type of oil used, the proportion and type of excipients (e.g., benzyl benzoate and benzyl alcohol), injection site, injection depth, route of administration (intramuscular vs. subcutaneous), individual metabolic differences, lifestyles and health, and interactions with concomitant medications. While some of these factors may be partially captured in the model's uncertainty when data is abundant and derived from multiple studies under varying conditions, this is rarely the case. Many of these factors also apply to other routes of estradiol administration, such as transdermal, oral, and sublingual. Efforts are underway to improve and generalize the models to better reflect this variability, though their accuracy and scope will always be constrained by the availability and quality of the underlying data.

All pharmacokinetic data used to infer intramuscular models have been manually redigitized from scratch from the original studies cited in the tfs meta-analysis. Where possible, per-patient data were further segmented into individual datasets rather than represented by their global average. Please consult the full list of references for a comprehensive account of all data sources.

Additionally, we employ a distinct, process-centric strategy for handling baseline data. While the TFS simulator applies a global offset to force the first data point to zero during preprocessing, our approach leaves the data unaltered and incorporates a decaying contribution to capture baseline dynamics. This contribution is represented by a simple structure that transitions from a constant level before administration to a decaying exponential afterward, which is then combined with the full three-compartment pharmacokinetic model. Together, these components form the overall estradiol curve, describing the exogenous administration of estradiol esters while seamlessly accounting for uncertainty in the baseline data. This approach provides a more accurate representation of the elimination process and eventual suppression of endogenous estradiol production, while naturally resolving the issue of negative levels that can arise with global offset corrections.

Note that pharmacokinetic data for estradiol enanthate (een im) and intramuscular estradiol undecylate (eun im) are substantially sparser compared to other esters. The data for estradiol enanthate comes entirely from studies on Perlutal from the 80s and 90s. The data for estradiol undecylate comes from only two studies (Vermeulen 1975 and Geppert's 1975 thesis) which both stopped measuring estradiol levels at the 2 week mark, thus preventing the model from capturing the full pharmacokinetic profile of the elimination phase and with it an accurate estimate of the terminal half-life.

The model for subcutaneous estradiol undecylate depots using castor oil (eun casubq) was inferred by augmenting the eun im and een im models with sparse self-reported community data (n=4). As a result, its predictions are associated with high uncertainty.

The once-weekly (patch ow) and twice-weekly (patch tw) patch models were derived from two studies by Houssain et al. and drug labels for Climara, Mylan, and Menostar matrix patches. See the list of references above. Based on insights from self-reported community data, it is important to note that both models significantly underestimate uncertainty, which is likely closer to ten times greater than currently represented. Future updates will aim to address this discrepancy. Additionally, the interface currently does not allow for adjustments to the patch wearing period (they are fixed at 3½ and 7 days) though this functionality is planned in future updates.

Menstrual cycle data were sourced from Stricker et al. 2006. Estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) data are available for download.

Target ranges for hormone levels are based on guidance from the WPATH Standards of Care, Version 8 and the Endocrine Society’s Clinical Practice Guideline.

Note on "inappropriate WPATH regimens" presets

The WPATH Standards of Care (Appendix C, page S254) lists several hormone replacement therapy (HRT) regimens for transfeminine individuals. However, some of these recommendations may not align with WPATH's own guidelines and could even pose potential risks. Here's a breakdown of the issues.

1. Issue with 5-30 mg intramuscular injections every 2 weeks:
• The half-life of estradiol valerate (EV) and estradiol cypionate (EC) are approximately 4 and 8 days, respectively. Administering injections every two weeks necessitates higher doses, leading to significant fluctuations in hormone levels. This can result in very high levels shortly after the injection and very low levels before the next dose, potentially causing mood swings in susceptible individuals and risking the reactivation of testosterone production in the last few days leading up to the next injection.
• At the lower dose limit (5 mg every 2 weeks), estradiol levels may fall below the threshold for monotherapy after approximately 7 days, risking the restart of testosterone production and estradiol levels dropping below 100 pg/mL, which contradicts WPATH's recommended levels.
• At the upper dose limit (30 mg every 2 weeks), estradiol levels may spike dangerously high (upwards of 2,000 pg/mL with EV and 1,000 pg/mL with EC), increasing the risk of thrombotic events in predisposed individuals.
2. Issue with 2-10 mg intramuscular injections every week:
• At the lower dose limit (2 mg weekly), estradiol levels may remain consistently around 100 pg/mL throughout the week with EC and below 100 pg/mL during the second half of the week with EV, potentially necessitating the use of an anti-androgen to suppress testosterone production or block its effects.
• Using the upper dose limit (10 mg every week), estradiol levels may consistently exceed 300-400 pg/mL, significantly higher than WPATH's recommended levels.

For a more detailed analysis, readers are referred to Rothman et al. 2024. Note that while these contradictions and issues have been widely recognized and discussed within the trans community for some time, the recent inclusion of these concerns in the medical literature represents an important development in aligning clinical guidelines with community experience and evidence.

Acknowledgements

Initial idea and development by alix. Code improvement and refactoring by Meringue. Help with data digitization from Annie. Additional help from Diamond, GearKite, Jess, Xea, and idk2848.

Encouragements, entertainment, feedback, and memetic pumping from
Torble Lea photino emily Izzy Ashley Sapphira

DISCLAIMER

This page, designed as a playground to explore estradiol pharmacokinetics, provides a simulation for informational and entertainment purposes only. The developer(s) cannot guarantee the accuracy of the predictions generated by the simulator. Users acknowledge that the software is offered "as is," without any warranties. The developer(s) assume no liability for direct or indirect damages, either physical, psychological, or otherwise, resulting from the use of the simulator. Users are strongly advised to exercise caution and seek professional medical advice for health-related queries.

estrannaise.js is entirely client-side. Your data, whether entered, imported, stashed, or loaded from a shared url, remains exclusively within your browser and will never be transmitted to the developer(s) or any third-party by our application.

mit license (c) 2025 alix
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If this kind of thing interests you, you can contact me on signal a1ix2.91 or by email _a1ix2_at_proton_dot_me_ (no underscores). For feedback, bugs, and feature requests submit an issue on github.

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