There Is No Standard Patient: Why Hormone Therapy Has to Be Titrated to the Person — Anatomy of Good Care (5/7)

The appeal, and the flaw, of the protocol

There is an understandable wish, in any area of medicine that has been chaotic or contested, for a clean protocol: a fixed starting dose, a fixed target, a fixed schedule, the same for everyone. It promises safety through standardisation and fairness through uniformity. Everyone gets the same thing, so no one can be accused of getting it wrong.

The trouble is that a protocol is built from a population, and no one is a population. An average dose is the right dose for the statistical centre of a group and the wrong dose for most of the actual humans in it. Standardising the input does not standardise the result — it just hides the variation behind a number that looks reassuringly fixed. In hormone therapy specifically, the gap between “the dose everyone gets” and “what that dose does in this person” is wide enough that pretending it away is itself a safety problem.

The same dose is not the same treatment

This is not a soft claim; it is measurable. Studies of feminizing therapy have found that guideline-concordant dosing produces a broad range of serum estradiol and testosterone levels, frequently with the two not even moving together — a patient can sit on target for one and far off for the other on exactly the recommended regimen [1][2]. Formulation compounds it: injectable estradiol given at guideline doses can land in supratherapeutic territory — particularly depending on the ester used and when in the dosing cycle the sample is drawn — while the same nominal dose by another route lands somewhere else entirely [2]. Route changes the pharmacology, not just the convenience — oral estrogen, for instance, behaves differently on its first pass through the liver than transdermal does [3].

The clinical consequence is simple to state and easy to forget: the dose is what you give; the level and the lived effect are what you get; and the relationship between them is individual. Two people on identical prescriptions are not on identical treatment. Which means you cannot manage the outcome by fixing the input — you have to look at the person and titrate. And titration reads more than the number: it is guided by clinical response, side effects, the person’s priorities, and safety monitoring, not by a lab value alone.

The target is a range to steer by, not a number to chase

The familiar targets — testosterone suppressed below roughly the cisgender female range, estradiol within a premenopausal band — are genuinely useful as orientation: therapeutic reference ranges rather than treatment goals in themselves. But they are guides, not finish lines. UCSF’s guidance is candid that the estradiol target rests largely on expert opinion, may be overly conservative, and that pushing estradiol higher does not buy additional feminization once androgens are adequately suppressed [4]. In other words, the goal is not to make a number on a lab report as large or as “perfect” as possible. It is to achieve the changes the person is seeking, safely — and then to stop optimising a figure that has stopped meaning anything new.

This is the same principle the monitoring picture keeps returning to: the level is information in service of the patient, read alongside how they actually present, not a target to be hit at the cost of the person attached to it.

The goal itself is individual

Even if every body metabolised hormones identically, a rigid protocol would still fail to meet everyone’s needs, because patients are not seeking the same destination. Some want the fullest possible degree of change; some want specific effects and not others; some — including many non-binary and genderqueer people — are seeking a particular, partial, or carefully calibrated embodiment rather than a standard endpoint, and may need regimens tailored differently from the binary defaults [5]. There is no single correct endpoint, within the boundaries of safe practice, to titrate toward — because “correct” is defined by the person’s own goals for their body.

This is not a fringe accommodation bolted onto the standards; it is the standards. The current WPATH Standards of Care are explicitly individualised and flexible by design, framed around shared decision-making, and state plainly that their criteria are clinical guidelines that professionals may modify in consultation with the person — a deliberate move away from rigid rules toward tailored, evidence-based recommendations [6]. The most recent edition is also the first to carry a dedicated chapter on non-binary care, precisely because one default does not fit a heterogeneous population [5][6]. The evidence base for non-binary regimens specifically remains thinner than for the binary pathways, which makes shared decision-making all the more important here [5].

What individualisation is not

It is worth being clear, because the word gets misread. Titrating to the person is not “anything goes,” and it is not the absence of standards. The safety floor does not move: the same monitoring, the same risk awareness, the same thresholds for acting on a haematocrit or choosing a lower-risk route apply to everyone. Individualisation operates within those guardrails, not instead of them.

And done properly it is the more demanding practice, not the more permissive one. A protocol can be administered; individualised care has to be thought. It requires reading this person’s levels, this person’s response, this person’s goals, and adjusting — which is harder, slower in attention if not in time, and far less automatable than handing out a fixed dose. The rigour does not disappear when the rigidity does. It moves from the rulebook into the clinician’s evidence-based judgement, where it belongs.

The point

A protocol treats the average as if it were the patient. Care treats the patient as the patient. The standard worth holding is not a single dose hit uniformly across everyone who walks in — it is the discipline of fitting the treatment to the person in front of you, their body and their goals, inside the safety limits that protect them.

There is no standard patient. There is only this one. Good hormone therapy is what happens when the treatment is built around that fact rather than against it.

Sources

1. Choice of Hormone Assay to Monitor Feminizing Gender-Affirming Hormone Therapy. Endocrine Practice, 2025; PMID 40945660 (the dose/route sub-analysis covered 573 individuals). — Guideline-concordant feminizing dosing yields a wide range of serum estradiol and testosterone levels, frequently discordant with one another, with substantial variation by route (a demonstration of measurement and response variability across formulations, not evidence that the reference targets are themselves wrong). (Trans-specific; adults.)
2. Carlson SM, Dominguez C, Jeevananthan A, Crowley MJ. Follow-Up Estradiol Levels Based on Regimen Formulation With Guideline-Concordant Gender-Affirming Hormone Therapy. Journal of the Endocrine Society, 2025; 9(3):bvae205; doi:10.1210/jendso/bvae205; with Injectable Estradiol Dosing Regimens in Transgender and Nonbinary Adults (PMC11957913). — In this single-centre cohort, guideline-concordant dosing did not consistently produce guideline-recommended levels: most parenteral follow-up measurements exceeded the reference range (91% supratherapeutic) and most transdermal measurements fell below it (70% subtherapeutic), illustrating how formulation and the timing of sampling shape measured concentrations. (Trans-specific; adults; single-centre observational data.)
3. UCSF Gender Affirming Health Program, Overview of feminizing hormone therapy. — Route alters pharmacology (e.g. oral estradiol produces relatively more estrone via first-pass hepatic metabolism than parenteral forms), one mechanism by which the same nominal dose differs by route. (Trans-specific; adults.)
4. UCSF Gender Affirming Health Program, Overview of feminizing hormone therapy. — The estradiol target is expert-opinion-based and possibly overly conservative; no evidence that higher estradiol produces additional feminization once androgens are adequately suppressed. (Trans-specific; adults.)
5. Castelijn JM et al. Prevalence of gender-affirming hormone therapy in non-binary and genderqueer individuals: a systematic review and meta-analysis. Endocrine, 2025; 90(2):420–426; doi:10.1007/s12020-025-04381-x. — Current guidelines focus largely on binary individuals and provide limited recommendations for non-binary and genderqueer people, who are a heterogeneous group needing more personalised counselling and treatment strategies; the evidence base for this group remains more limited than for binary pathways. (Trans-specific; adults.)
6. Coleman E et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 2022; 23(Suppl 1):S1–S259; doi:10.1080/26895269.2022.2100644. — Explicitly individualised, flexible, shared-decision-making framework; criteria are clinical guidelines that professionals may modify in consultation with the person; a deliberate move from rigid rules toward tailored, evidence-based recommendations; first WPATH edition with a dedicated non-binary chapter. (Trans-specific; adults and youth — principle of individualisation cited in the adult frame.)