Venous Thromboembolism, Myocardial Infarction and Ischaemic Stroke in Feminising Hormone Therapy — Evidence Review (ER-018)

Evidence Review · ER-018

Abstract

Method. This is a narrative Evidence Review, not a systematic review, grading the certainty of the evidence on venous thromboembolism, myocardial infarction and ischaemic stroke in feminising gender-affirming hormone therapy. It uses a declared four-axis editorial scheme — causal attribution, observed effect size, clinical importance, population directness — and holds the evidence question apart from any policy or prescribing question. Certainty marks are editorial judgements, not formal GRADE ratings. Sources are appraised for cohort independence; a study-overlap matrix identifies where a literature rests on one clinic’s registry.

Findings. A reproducible association with higher VTE incidence is present, approximately twofold across the principal contemporary analyses. In Kaiser’s status-defined overall transfeminine cohort, identified by transgender status rather than restricted to confirmed oestrogen recipients, hazard ratios were 1.9 versus men and 2.0 versus women; the expanded Kaiser hormone-initiation cohort had hazard ratios of 1.7 and 1.8; and Amsterdam’s hormone-treated cohort had standardised incidence ratios of 1.81 versus men and 1.74 versus women. These are different estimands and exposure definitions, and are not pooled. In the Kaiser STRONG cohort, adjusted eight-year risk differences in the overall transfeminine cohort were 16.7 additional VTEs per 1000 versus matched male and 13.7 per 1000 versus matched female comparators; these are cohort-specific and should not be generalised to patients with different baseline risk. In available series, cases were disproportionately observed in older and more comorbid participants, but individual-level effect modification has not been established, and the proportion of the association causally attributable to contemporary prescribed oestradiol remains uncertain. High-dose ethinylestradiol is strongly implicated in the larger historical associations and is deprecated; in the one direct trans comparison, the studied 17β-oestradiol regimens produced substantially smaller haemostatic change, though contemporary regimens are not haemostatically inert. Route and molecule are the best-reasoned levers, though the trans-specific outcome evidence is thin and rests substantially on cisgender extrapolation. For arterial outcomes, the 2026 Amsterdam registry analysis found lower myocardial-infarction incidence (SIR 0.50) and no statistically different ischaemic cerebrovascular-accident incidence (SIR 0.94) against standardised male reference rates, and Kaiser found no overall MI excess against men, while the expanded Kaiser initiation cohort found higher ischaemic-stroke incidence than matched cisgender referents (HR 2.0 vs men, 2.3 vs women; Goodman & Zhang 2021, a PCORI final research report in the same Kaiser lineage); these are external-comparator findings, not estimates of the causal effect of therapy, broader meta-analytic evidence is not uniformly reassuring for stroke, and no cardioprotective effect has been established. Management follows guideline and expert-synthesis positions (Hembree 2017; ASH 2024): no routine primary thromboprophylaxis, routine thrombophilia screening of unselected patients before therapy is not recommended, while selective testing may be appropriate where a personal or relevant family history means the result would change management, and — where oestrogen continues after a VTE — continued full-dose anticoagulation per the ASH expert review.

This review is not a prescribing protocol and not a policy position, and no clinical or policy decision should rest on it alone.

Note on the certainty scheme — an ER-018 exception to house style

Eden Openly’s house standard is a three-axis, reader-facing traffic-light scheme of our own design (robust / moderate / limited), used across ER-001–ER-017. ER-018 is a declared exception. Because this topic turns on a distinction the field routinely collapses — between whether a treatment caused an outcome and how large that outcome is — ER-018 uses a four-axis scheme: causal attribution · observed effect size · clinical importance · population directness. Editorial, disclosed, and not formal GRADE. The house three-axis scheme remains standard for the corpus; ER-018 escalates for analytical fit and says so rather than switching silently.

What these labels are, and are not. They describe the author’s structured interpretation of the evidence included here; they are not estimates of systematic-review certainty. Study identification was purposive, no uniform study-level risk-of-bias instrument was applied, and the judgements are a single author’s, without inter-rater validation. A reader should read “robust” as “robust on the evidence assembled and the reasons stated”, not as the output of a reproducible grading procedure.

Decision rule:

• Causal attribution — robust: multiple independent designs, major confounding addressed, temporality/dose-response; moderate: consistent association, residual confounding plausible, no internal untreated comparator; limited: single source, sparse, or heavy extrapolation; not established: no usable evidence either way.
• Observed effect size — the named magnitude (HR/SIR/OR/risk difference or marker change) and its uncertainty where available. It is descriptive, not a separate formal certainty scale; different estimands, endpoints and populations are not pooled, and where no common magnitude is defensible that is stated. A marker change and an incidence ratio are never commensurable.
• Clinical importance — for an outcome, its seriousness and actionability: whether, if it occurred, a patient would notice it and a clinician would act; for a finding about a modifiable factor, whether it would change what a clinician or patient does. It is independent of certainty and of size: the absolute, treatment-associated burden, which depends on baseline risk, is graded under observed effect size, not here.
• Population directness — direct (trans), mixed, or indirect (cisgender extrapolation, flagged at use).

Estimand glossary:

Numerically similar values from different estimands are not the same finding. ER-018 names the estimand beside every figure and does not pool across them.

1. In brief

The findings, in one screen. Written so a clinician who reads nothing else is not misled.

3. What this review is, and is not

This review holds a single even-handedness commitment: to treat “the evidence is too weak to show benefit” and “the evidence is too weak to show harm” as the same kind of claim, judged by the same rules. A reassuring finding is held to the same scrutiny as an alarming one; over-claiming safety is the same error as over-claiming risk. Where the evidence is thin, this review grades it thin in both directions.

It is a narrative review, not a systematic review (see Limitations and the methods statement). It does not claim to have captured every relevant study, and its certainty marks are editorial judgements, not formal GRADE ratings.

4. Scope

In scope: venous thromboembolism (deep vein thrombosis and pulmonary embolism), myocardial infarction, and ischaemic (cerebrovascular) stroke, in the setting of feminising (oestrogen-based) gender-affirming hormone therapy. The review is organised on three axes — molecule (ethinylestradiol vs conjugated equine oestrogen vs 17β-oestradiol), route (oral, transdermal, injectable, transmucosal), and population (trans-direct evidence vs cisgender extrapolation).

Out of scope, and why: heart failure, arrhythmia and all-cause or cardiovascular mortality (not graded here — the outcome-specific evidence is treated separately from the composite “cardiovascular disease” endpoints that dominate parts of the literature); bone health, fertility, breast effects and hair (each the subject of a separate planned Evidence Review); and masculinising testosterone therapy, whose thrombotic and erythrocytosis profile is a distinct topic signposted to its own review (ER-023). Where a cohort reports a composite “any cardiovascular disease” outcome, that composite is not treated as a venous-thromboembolism estimate.

5. Limitations

Stated before any finding, so the reader weighs the conclusions accordingly:

• This is a narrative review, not a systematic one: no registered protocol, no exhaustive search, no dual screening, no uniform risk-of-bias instrument. It makes no claim of completeness. (Full method in the methods statement below.)
• The certainty marks are editorial, using a declared four-axis scheme (causal attribution · observed effect size · clinical importance · population directness) as an exception to the corpus’s house three-axis standard. These are editorial certainty judgements, not formal GRADE ratings; they are one author’s structured interpretation, without inter-rater validation or a uniform study-level risk-of-bias assessment.
• Much of the route, molecule and post-VTE-management evidence is extrapolated from cisgender populations and is flagged as such at every use; there is no trans-specific outcome trial isolating route or molecule.
• Nine sources are read in abstract only and are flagged at use: the post-v1.0 all-gender and survey studies of Part C (Balshi, Huo, Federico, Saleh), the Franco-Moreno 2025 systematic review, the Slack 2024 chart review (B1), the Vecchiato 2026 expert opinion (B1, Part C) and the two mechanism studies Lim 2020 and Bar-On 2026 (Part A). None carries a grade alone. The historical “45-fold” and “twentyfold” figures are verified in their primaries and are not used in the graded body.
• No longitudinal VTE-incidence cohort provides a clean internal untreated transfeminine counterfactual, so the separation of treatment effect from era, population and co-medication is inferential for the venous findings; for arterial outcomes one analysis contrasts trans people with and without recorded hormone therapy, with the limits stated in Part C (Streed 2025).

6. Cohort-independence note

Say this before the reader counts studies. The load-bearing comparative VTE-incidence estimates rest on two independent cohort lineages — Kaiser Permanente (US, the STRONG cohort / Getahun) and Amsterdam (Netherlands, the ACOG cohort / van Zijverden). Additional independent trans-direct datasets exist (the Danish register cohort of Glintborg 2022; the chart review of Slack 2024), but they do not estimate the same incident treatment-associated effect and are not treated as co-equal magnitude estimators. Numerical agreement between the two lineages is independent replication of a similarly directed association, though both remain vulnerable to some shared classes of observational bias — external comparators, and no longitudinal VTE-incidence cohort provides a clean internal untreated transfeminine counterfactual.

Agreement within a lineage is not. The Amsterdam figures across decades (van Zijverden, which supersedes Nota, and the historical van Kesteren and Asscheman) are one institutional cohort re-analysed, not independent replications; and the widely cited prevalence meta-analysis (Totaro) pools Getahun, Nota and van Kesteren, so it can never serve as independent confirmation of any of them. The coagulation-mechanism evidence (Part A) is concentrated in the Amsterdam clinic and the ENIGI network, with overlap within the larger European datasets. The independent evidence is two cross-sectional studies (Porto Alegre, Melbourne) and a small prospective Israeli pilot, two of them appraised at abstract level; all supply external laboratory observations, not independent clinical-VTE replications. A third national cohort (Glintborg, Denmark) is genuinely independent but reports a broad composite cardiovascular outcome, not a clean venous-thromboembolism estimate, and is used accordingly.

The full mapping — who supersedes whom, who pools whom, and which figures are one dataset wearing several citations — is set out in the study-overlap matrix below.

Declarations

7.1 Competing interests

Position. The author is a transgender woman receiving gender-affirming hormone therapy and a dermatologist, with a personal stake in transgender health and the commitments set out below, and treats these as potential sources of motivated reasoning. A plausible risk is preferential detection or weighting of congenial findings, but the direction and magnitude of any actual bias cannot be known in advance, and over-correction is as possible as confirmation. The safeguards are the paper’s published methods, not the disclosure. Nothing in this paper rests on the author’s clinical standing; every judgement is published with its reasoning, for anyone to check.

Declared prior (an intellectual interest, declared as a competing interest). “Eden is a transgender woman receiving gender-affirming hormone therapy, and a dermatologist. She holds a declared prior in favour of access to gender-affirming hormones for adults, and of adolescent access to puberty blockers and gender-affirming hormones; the method is designed to make any resulting bias more visible and auditable, and findings that cut against that position are reported at full weight.”

Competing interests (as at 14 October 2026; any change is declared as an Update in this paper’s revision history. The definitive, dated list is kept at edenopenly.com/about/declared-interests).

(a) The author is the founder and sole funder of a non-profit transgender healthcare and education organisation. The author is developing its clinical services, including its clinical protocols, and its education programmes, and is recruiting its clinical staff. Its education programmes include patient and family resources, school resources, and training for healthcare professionals in the organisation’s own standards of care, which address questions in the same field as the guidelines and standards of care this series appraises. The organisation is not a party to this paper and has no role in it. The findings of this paper may inform its clinical protocols and educational material; that is a further interest in the findings, declared here.

(b) The author is the founder and sole funder of Eden Institute (edeninstitute.kr), a transgender health research institute in South Korea, which is intended to include a biobank and associated data infrastructure. It provides no funding for this paper and has no role in it.

(c) The author, through Eden Openly, is engaged in public correspondence and requests concerning the NHS Wales Joint Commissioning Committee’s Welsh Gender Service surgical referral pause, including written approaches to the Committee, requests under the Freedom of Information Act 2000, correspondence with Llais, and submissions to Senedd committees. Eden Openly publishes critical analysis of the decision at edenopenly.com/welsh-gender-service and describes itself as a party to the matter; the correspondence is published at edenopenly.com/wgs-correspondence. This is a public position on the evidence base for gender services. The author is not a party to any litigation and has no present intention to become one; any change is declared as an Update.

(d) The author, through Eden Openly, is engaged in parliamentary advocacy on the Health Bill’s single patient record provisions: written evidence to the House of Commons Public Bill Committee (published on the parliamentary record as HB130), a submission to the House of Lords Delegated Powers and Regulatory Reform Committee, and briefings to members of the House of Lords proposing an amendment. The advocacy concerns the confidentiality of, and access to, patient records, including a competent young person’s confidential control of their own record. It argues against provisions drafted by the Department of Health and Social Care and engages NHS England’s conduct. Everything filed is published at edenopenly.com/single-patient-record. This is a public position taken before Parliament; it is continuing, and any change is declared as an Update.

(e) The author, through Eden Openly, is conducting a structured appraisal of the Cass Review and the associated University of York systematic reviews. Its methods, stage and record are published at edenopenly.com/cass-review. The appraisal is a public undertaking to reach judgements on evidence and recommendations in the same field, and where this paper’s evidence overlaps its objects, the two may reach judgements on the same studies. ER-018 primarily concerns adult feminising therapy. Some cited studies permit or include participants under 18 — both Saxby 2026 datasets begin at 15 years, and da Cruz 2025 admitted participants aged 16 and over — while the Kaiser cohorts graded in Parts B and C enrolled participants aged 18 and over; other cohorts’ age boundaries are stated at use where they matter. This review does not establish the safety or effectiveness of adolescent treatment and does not substitute for an adolescent evidence appraisal. The Cass appraisal concerns evidence and recommendations for under-18s; no source graded as cardiovascular evidence in ER-018 is an object of that appraisal.

(f) The author’s published evidence reviews at Eden Openly assign quality and certainty grades to evidence that may overlap the subject of this paper. Where they do, they are a prior commitment on the same evidence, stated study by study, and are declared here as an interest. This paper overlaps ER-005 (Feminising Hormone Therapy), which grades venous and arterial outcomes from the same cohort lineages, and ER-008 (hormone monitoring and target ranges).

(g) The author, through Eden Openly, reports errors in published literature to the journals and bodies responsible for them, and records each report and its outcome in the Evidence Transmission Register, published at edenopenly.com/editorial/transmission-register. No report has been made concerning a source cited in this paper (see §7.5).

(h) The author is a co-owner of, and the lead researcher at, a commercial business that develops skincare products and sells them to the general public through ordinary retail channels. The author is also planning, as a joint venture with a surgeon, a general aesthetic dermatology and surgery hospital; it is not open, may not open, and would not target transgender patients. The author may receive a financial return from both. Neither is a party to this paper, provides funding for it or has a role in it. These are the only commercial interests declared here.

Funding. This paper is unfunded. The author accepts no third-party funding for research, publication or appraisal activity, as a standing policy, and neither does (a) nor (b). All costs, including any external review, are paid personally by the author. The author’s funding of (a) and (b) is a financial interest in organisations working in transgender health, whose operating environment the subject of this paper may affect. (h) is a commercial interest, present and planned, from which the author may receive a financial return.

The declared prior and interests (a) and (b) create a plausible incentive toward findings favourable to access to gender-affirming care, and each is disclosed for that reason. (e) creates a plausible incentive toward findings on shared evidence that are consistent with the author’s appraisal of the Cass Review. (c) and (d) are public positions on gender-service policy and patient-record policy respectively; they bear on this paper only so far as its findings touch those policies. (f) and (g) are disclosed as prior commitments on the same evidence, not as incentives of stated direction; their direction depends on the grades and reports concerned. (h) bears only where the paper concerns skin, hair or aesthetic treatment, which this paper does not.

ER-018 direction note. The review was written under adversarial review with symmetric bias-checking as its explicit standard, and it reaches several conclusions the author did not want — among them that the venous thromboembolism association is reproducible and not to be explained away, and that the lower observed incidence of myocardial infarction is not demonstrated cardioprotection and must not be presented as a benefit of therapy. The declared prior was disclosed to the external reviewer before drafting began.

Rationale. The stake is not concealable and was never concealed. Declaring it before the findings is what allows the findings to be read as findings. A reader who knows the bias and can still check every number is in a stronger position than one who has to guess. The mental-health benefit — the finding the author would most prefer to be true — is graded in its own front-matter declaration at least as conservatively as the harms, precisely because this interest bears on it.

7.2 Correction record

This record is not an apology; it is the credential. For an author without institutional affiliation, a visible record of self-correction is the available evidence of method. Each item states what was wrong, where the error came from, who caught it, and what changed.

The standing pattern

Within this review’s production history, most identified errors arose during summarisation, inference, drafting or secondary-source transmission — secondary-source characterisations read in place of primaries, an ecological finding converted to an individual one, a vivid number reached from memory, an interpretation adopted rather than attributed — rather than from inaccuracies identified in the primary studies themselves. Sections built directly on primaries read in full held up under adversarial review; the failures clustered where the text summarised, inferred, or reached. This is an observation about the errors detected during production of this review, not an estimate of their distribution across the field.

Substantive corrections

1 · Omission of the contemporary Amsterdam analysis (van Zijverden 2026).
Wrong: Parts B and C were built on Nota 2019 without integrating the superseding 2026 registry analysis. Source: the paper was in the archive and flagged in working notes but left unread — a gap in the author’s own process, not the literature’s. Caught by: external reviewer, round 1. Changed: van Zijverden read in full and made the spine of the venous and arterial estimates; VTE magnitude recalibrated to ≈1.8–2.0×; the arterial section rebuilt (MI SIR 0.50); the unsupported “male-substrate” construct replaced with the study’s own framing.

2 · The “ethinylestradiol-free window” factual error.
Wrong: the text claimed van Zijverden’s 2012–2022 event window meant the cohort was EE-unexposed, and that gate G1 was therefore “discharged twice.” Source: an inference not supported by the paper — the cohort initiated therapy from 1972 and the authors performed no past-EE sensitivity analysis. Caught by: external reviewer, round 2; confirmed against the primary’s own limitation text. Changed: corrected to “not an EE-naïve cohort”; G1 downgraded to “partly addressed.”

3 · Arterial overclaim (the body contradicting its own disclaimer).
Wrong: Part C stated feminising therapy “may lower MI risk” while a provenance note simultaneously disclaimed any causal reading. Source: the author’s principal overclaim migrated from venous to arterial while the venous causal language was being disciplined — the symmetric-bias standard failing on the reassuring side. Caught by: external reviewer, round 3. Changed: full de-causalisation — MI 0.50 reported as observed comparator incidence, the study authors’ interpretation reported as a hypothesis rather than adopted, the grade table reconciled with its disclaimer.

4 · Ecological fallacy in the concentration and stratification sections.
Wrong: Totaro’s study-level age and duration subgroups (< 37.5 years, < 53 months) were converted into individual-level risk statements (“negligible in young patients”). Source: an aggregate meta-regression read as individual-participant data. Caught by: external reviewer, round 1. Changed: reframed as aggregate associations with no individual threshold, in B1 and D.1; the data-derived cut-offs explicitly denied clinical-rule status.

5 · Internal contradiction on the ethinylestradiol mechanism.
Wrong: A.3 stated molecule and dose could not be separated; B2b later called the EE effect “molecular.” Source: drafting inconsistency across tranches. Caught by: external reviewer, round 1. Changed: B2b corrected to “high-dose EE, molecule and dose not separable.”

6 · An unsupported sublingual peak figure (≈ 800 pg/mL).
Wrong: a specific numerical peak was introduced in a wording pass, unverified. Source: a figure reached from memory rather than a primary — precisely the failure the citation-verification rule exists to prevent, committed by the author while running that discipline on others. Caught by: external reviewer, round 4. Changed: the number removed entirely — and not replaced with the reviewer’s alternative figures, which were themselves unverifiable against any held primary; a qualitative statement and a source-gate flag stood in its place.

7 · Exact percentages from an unobtained source (Seal 2012).
Wrong: exact subgroup VTE percentages were retained from an abstract-level source not obtained in full. Source: the same failure mode as item 6 — precise figures resting on an unread source. Caught by: external reviewer, round 5, and recognised by the author as identical in kind to item 6. Changed: the percentages were withheld pending the primary and the qualitative ranking retained (superseded by U4: Seal 2012 was filed and read in primary at v1.1).

8 · Incorrect hazard-ratio definition.
Wrong: the estimand glossary — built to prevent estimand confusion — defined a hazard ratio as a relative event rate over follow-up, which describes an incidence-rate ratio. Source: author error. Caught by: external reviewer, round 4. Changed: corrected to the instantaneous-hazard definition with the proportional-hazards caveat.

9 · Mental-health benefit overclaim.
Wrong: the text stated therapy “substantially reduces depression and suicidality,” conflating ideation, attempts and mortality and overstating the suicide-specific evidence. Source: a benefit-direction overclaim — the symmetric-bias standard failing toward the author’s own position. Caught by: external reviewer, round 1. Changed: narrowed to dysphoria, well-being and depressive symptoms with an observational-evidence qualifier; the claim was relocated to a graded front-matter declaration held to the same standard as the harms.

10 · Asymmetric ascertainment scrutiny.
Wrong: detection-bias scrutiny was applied to the reassuring arterial finding but not to the alarming venous one. Source: the author’s own skepticism running harder on the reassuring side than the alarming side. Caught by: external reviewer, round 3. Changed: a symmetric ascertainment caveat added to the venous signal; subsequently (round 4) both were disaggregated into distinct mechanisms — diagnostic ascertainment, preventive care, registry misclassification — rather than lumped as “bias.”

11 · The “natal-male substrate” construct.
Wrong: arterial risk was explained via a “natal-male substrate baseline” — an underdefined construct that implied biological determinism. Source: the author’s compressed-metaphor style tipping into an unsupported explanatory claim. Caught by: external review, round 1. Changed: replaced with the comparator description and an explicit statement that the pattern does not identify its mechanism.

12 · Cyproterone regional-availability error.
Wrong: cyproterone was described as unavailable across “North America.” Source: collapsing US non-approval into a blanket regional claim. Caught by: the author, prompted by a patient’s report of Canadian prescription. Changed: corrected to jurisdiction-specific — approved in Canada and Europe (off-label for feminising therapy), never approved in the US — verified against the Health Canada-authorised product monograph.

13 · Two unvalidated mechanistic clauses.
Wrong: spironolactone “haemoconcentration” (not an established VTE mechanism) and oestrogen “RAAS-mediated blood-pressure rises” — the latter substituting the author’s own unvalidated narrative for the study’s over-favourable one. Source: mechanism asserted in place of evidence. Caught by: external reviewer, round 4. Changed: both removed or softened to route/dose-dependent.

Corrections logged during earlier production (pre-review)

14 · The “45-fold” figure — analysis revised on further reading. Initially hypothesised to be a probable count-to-fold conflation of van Kesteren’s 45 cases with a fold-change. That hypothesis is now weakened: two independent 2024 secondary reviews (ASH; Nolan & Cheung) both attribute “45-fold (occurring in 6.3%)” specifically to Asscheman 1989 for a 100 µg ethinylestradiol + 100 mg cyproterone regimen, which suggests the figure is a genuine (if extreme, obsolete-regimen) statistic from that primary rather than a transcription artefact. At that stage it remained unverifiable — Asscheman 1989 had not been obtained — and could not be reconciled with the same Amsterdam cohort’s later ~20-fold (van Kesteren) without the primary. Handling at that stage: quarantined pending verification of Asscheman 1989, attributed not asserted, and not used in the graded body; the evidence-transmission appendix documents the attribution chain and the revised (non-conflation) reading. This entry is itself a correction of an earlier correction — recorded as such, because revising a hypothesis on new evidence is the method, not a lapse. 15 · APC resistance downgraded from “validated predictor” to “associated phenotype.” 16 · Burgoon (cited in v1.0 as “Cunningham”) comorbidity odds ratios given their confidence intervals and hypothesis-generating framing. 17 · The “twentyfold” van Kesteren figure marked attributed-not-asserted (primary not obtained); verified in primary at v1.1 (item 24).

Corrections at version 1.1 (post-deposit accuracy review, 13 October 2026 UTC)

18 · Two primary references misattributed. Wrong: the J Clin Med 2026 Duke cohort was cited as “Cunningham 2026” with an incorrect title (its first author is Burgoon; Cunningham is second author), and the van Zijverden 2026 European Heart Journal cohort was given the title and author order of the same group’s 2024 meta-analysis. Source: reference metadata carried from a characterisation rather than from the archived primaries. Caught by: post-deposit accuracy review. Changed: cited as Burgoon 2026 throughout; both reference entries corrected. Findings unaffected.

19 · Pyra 2020 outcome reported as venous thromboembolism. Wrong: Pyra’s “thromboembolism” is a composite of ICD-10 codes I26, I65, I66, I80–I82 and I87, which includes arterial (cerebral and precerebral) and superficial venous events; the medroxyprogesterone estimate rests on a single event; the concentration analysis was given as N=4402 (all patients) rather than the 2029 trans women modelled; and the B3 provenance line still recorded Pyra as not obtained although it was read in primary before v1.0 was deposited. Caught by: post-deposit accuracy review. Changed: B2c, B3a, B3 provenance, the claim map, the overlap matrix and Appendix Case 2 reworded. The B2c inference — that an accompanying progestogen should not be assumed haemostatically inert — stands, held more lightly.

20 · Figures misstated against their primaries. Wrong: the intramuscular-oestradiol count (B3b: two of six unprovoked and three of sixteen overall, not “two of six … three cases”); the Kozato cohort (407 primary vaginoplasty cases, 190 suspended and 212 continued, not “402 gender-affirming surgical cases”); the Getahun total (102,421, not 102,417); Toorians’ “stated dose–response” (a suggestion by cross-study comparison, not a tested finding) and its within-person design (not true of the oral-oestradiol arm); the Kuijpers 10 mg arm (n = 4); Nota’s smoking (“prevalence”, not “ever-smokers”), its stroke definition (which includes haemorrhagic stroke, TIA and subarachnoid haemorrhage) and its comparator (Norwegian only as van Zijverden describes it); the Kaiser early hazard (imprecise, not “near-null”); and the Giltay contrast (oral ethinylestradiol against transdermal oestradiol, so route and molecule are confounded). Caught by: post-deposit accuracy review. Changed: each corrected to its primary or published abstract.

21 · Guideline grades and regulatory scope misdescribed. Wrong: the Endocrine Society 2017 guideline was said to “recommend” oestradiol monitoring (Recommendation 3.3 is a grade-2 “suggest”); WPATH SOC-8’s “suggest” statements were called “conditional” (SOC-8 grades them weak), and a 12.11 supporting-text sentence was attributed to 12.14; the 2020 EMA cyproterone restriction omitted the sex-drive indication and the unchanged prostate-cancer use. Caught by: post-deposit accuracy review. Changed: wording aligned to the sources; the CMDh position (EMA/147755/2020) added.

22 · Claims without a cited source. Wrong: Part A graded oral oestrogen’s haemostatic shift “robust” on “cisgender RCT evidence” that ER-018 did not cite (ESTHER, which was cited, is a case-control study); the mental-health declaration graded the benefit without citing any source; D.4 stated an antiphospholipid-syndrome anticoagulant preference that its cited source does not contain; thrombophilia screening and primary prophylaxis were attributed to “general consensus” although a guideline and an expert synthesis held in the archive state them. Caught by: post-deposit accuracy review. Changed: Part A row A2 regraded moderate as to direction pending appraisal of the randomised marker trials; the mental-health declaration now cites Baker 2021, a systematic review that rates the evidence low, and its causal attribution is regraded from Limited–moderate to Limited — the symmetric standard applied to the finding the author would most prefer; the APS clause reduced to a specialist-referral statement; D.3 and D.4 cite Hembree 2017 and ASH 2024.

23 · Verification statement overstated. Wrong: §7.3 and §7.4 stated that every claim, number and citation had been verified against the primary source, which could not be true of sources read only in abstract or not obtained, and the verification pass had missed items 18–22. Caught by: post-deposit accuracy review. Changed: the statements now describe verification by source tier; drafting remnants (“at this draft”, “at sweep”, “candidate”, “remains to be built”) removed; the source counts in §7.3 corrected; reference titles for ASH 2024, da Cruz 2025, Giltay 2000, Manchkanti 2023, Rothman 2024 and Schutte 2022 corrected and missing DOIs added.

24 · The “45-fold” and “twentyfold” revisited (supersedes the handling recorded at items 14 and 17). Wrong: v1.0 called the 1989 primary unobtainable, held the conflation hypothesis open and treated the van Kesteren twentyfold figure as unverified. Source: neither primary had been read. Caught by: post-deposit accuracy review, with both primaries filed and read at v1.1. Changed: Asscheman 1989 (19 observed vs 0.42 expected among 303; 6.3%) and van Kesteren 1997 (45/816; SIR 19.56, 12.27–26.18) are both verified; the conflation hypothesis is refuted; van Kesteren’s own explanation of the fall (transdermal oestradiol advised over 40 from 1989) is recorded. Both figures are stated in B1’s historical anchor and remain outside the graded body.

25 · Interpretive overreach in the summary and body. Wrong: the abstract and “In brief” called the VTE association “real but modest”, presented the Kaiser eight-year risk difference as a general figure, and described “long latency” (“years, not weeks”) from case-conditioned time-to-event data; Part B said “two forces explain” the historical estimates and that the marker–outcome gap was “smaller and more explicable”, re-introducing a comparison A.5 rules out; Part C ranked testosterone suppression as “at least an equal candidate”, stated the arterial finding for the whole evidence base from one registry analysis, and called venous–arterial collapse “the commonest error”; B2b called conjugated equine oestrogen hidden inside “estradiol” and 17β-oestradiol “the low end”; Pyra’s nulls were written as “no association”; the Endocrine Society target was called “the physiological range” and its link to thromboembolic risk omitted; the mental-health declaration asserted that the benefit’s clinical weight exceeds most harms. Caught by: external review, 14 October 2026. Changed: each restated to what its source bears.

26 · Evidence currency. Wrong: v1.0 omitted syntheses and cohorts available within its own window — the 2024 cardiovascular meta-analysis (van Zijverden 2024), the 2025 VTE systematic review (Franco-Moreno 2025), the randomised route trials (Oger 2003; Post 2003), the trans-specific sublingual pharmacokinetic study (Doll 2022), the 2022 perioperative meta-analysis and 2024 surgical cohorts, the 2025 Veterans Affairs cohort (Streed 2025), and a February 2026 mortality cohort (Saxby 2026). Source: purposive discovery without a documented search. Caught by: external review and the v1.1 update search. Changed: each incorporated, with cohort overlap stated; Part A row A2 restored to robust as to direction on the randomised evidence, labelled indirect.

27 · Post-VTE management understated the cited expert position. Wrong: D.4 advised duration by standard provoked/unprovoked assessment without distinguishing continued from discontinued oestrogen, which could imply a finite course while exposure continues; ASH 2024 suggests concurrent full-dose anticoagulation if oestrogen continues and does not recommend stopping it. Caught by: external review. Changed: D.4 rebuilt around that distinction.

28 · Second external review: progestogen evidence misread, an axis applied against its definition, residual overclaim, and tables ahead of the prose. Wrong: (a) B2c read ESTHER as showing that progestogen class raises VTE risk and called Pyra’s progestin signal concordant with it, and D.2 cited “ESTHER’s progestogen-class signal” in the case for cyproterone as a haemostatic co-exposure; ESTHER found heterogeneity, with the elevation confined to norpregnane derivatives and the pregnane class — which includes cyproterone and medroxyprogesterone acetate — null (OR 0.9, 0.4–2.3). Correction 19’s statement that the B2c inference “stands” is superseded. (b) Clinical importance was defined as independent of size and certainty, yet VTE was graded “Conditional” on baseline risk and myocardial infarction and stroke “Moderate”. (c) Wording that correction 25 reported removed survived in B2 (“real … and slow”), Part D (“the venous association is modest”) and the mental-health declaration (“a real and modest venous risk”; “limited-to-moderate” attribution against a formal grade of Limited). (d) Tables and one management sentence claimed more than the prose: B2b ranked 17β-oestradiol “lowest”; B3 and D.2 called a VTE benefit of level targeting “presumptive”; D.2 graded the anti-androgen VTE benefit “limited” rather than not established; and D.2 asserted that individual risk factors “matter more” than formulation, a comparison no source quantifies. (e) Streed 2025 was summarised as a treated-versus-untreated contrast finding “no association”. (f) Mental-health population directness was graded Direct for a feminising-specific claim, although much of the evidence combines directions. (g) Row A2 stated first-pass mediation in its title rather than as the leading explanation. (h) §7.3 placed a conference abstract and secondary reviews under “read in primary (full text)”. (i) Li 2024’s outcome-table grouping (714/205/34) was presented as its regimen count (714/197/8). (j) WPATH’s perioperative supporting text was located at Statement 12.18 rather than under 12.19. (k) Slack 2024 was retrieved and left out, and Vecchiato 2026, retrieved by the 13 October search, was screened out as expert opinion while Skeith & Bates 2026 was included. (l) The version notice dated the first external review by a non-UTC date. Caught by: second external review, except (l), found in the author’s check. Changed: B2c and the D.2 cyproterone case rewritten, and lowest-dose advice decoupled from VTE; clinical importance redefined as outcome seriousness or, for a modifiable factor, actionability, with VTE, myocardial infarction and stroke regraded High and absolute burden moved to effect size; the residual wording replaced; the tables aligned with the prose; Streed restated as recorded versus no recorded therapy, with no statistically detectable association; mental-health directness regraded; A2 retitled; §7.3 split by source type; Li’s groups explained; the WPATH reference located; Slack added to B1 as a non-coequal counterpoint and Vecchiato as an abstract-level synthesis, with the independence claim narrowed to the load-bearing incidence estimates; D.3 and D.4 each given one clinical clarification; the search re-run.

29 · Third external review: the effect-size axis, comparator terminology and residual drift. Wrong: (a) The observed-effect-size axis requires a named estimand, yet the mental-health declaration graded effect size “Moderate” across scales it described as not poolable, and row A4 graded contemporary haemostatic change “small-to-modest” across heterogeneous markers. (b) The Amsterdam comparator, general-population men and women, was described as “cisgender” in the In brief, the B1 grade table and summary, and Part C (headings, C.1–C.3 and the claim map). (c) C.2 said there was “no cross-comparator excess” immediately after reporting higher point estimates against women. (d) The D.2 table graded blood pressure, lipids and glycaemia together with VTE risk factors as “robust”, contrary to D.1. (e) The arterial claim map and independence summary omitted the less reassuring pooled stroke estimate stated in Part C. (f) Reviews, guidelines and regulatory documents remained labelled “read in primary” in several provenance lists, and ASH 2024 was called “framing only” although Part D uses it directly for management. (g) Smaller wording: “legacy risk” for ethinylestradiol; “no risk-positive signal exists for cyproterone”; a “modest” unexcluded long-term stroke contribution; and item 14’s “Current handling”, superseded by item 24. (h) The search appendix did not say that narrative syntheses were retained selectively. Caught by: third external review. Changed: both effect-size grades restated without a magnitude; comparators named as male and female reference populations, with Kaiser’s matched cisgender and Amsterdam’s general-population rates distinguished; the C.2 sentence corrected; the D.2 row split into VTE and arterial factors; the claim map and summary aligned with Part C; “read in full” used for non-primary sources and ASH’s management role stated; the wording corrected; the selective-retention sentence added to the appendix; and a feminising-specific mental-health-treatment study (Saxby 2026, EClinicalMedicine) noted in the declaration’s scope, without a grade change.

30 · Fourth external review: the review’s account of its own method and scope. Wrong: (a) The appraisal rule said secondary sources were used for framing, locating primaries and (ASH) management, although Baker 2021 and Cooney 2025 directly support the mental-health declaration; the claim-map symbol ○ conflated source type with access. (b) Competing-interest statement (e) said ER-018’s evidence concerns adults, which ceased to be strictly true when correction 29 added a dataset including people aged 15–24. (c) The correction record and the transmission appendix stated as a field-wide thesis that errors are “overwhelmingly in transmission”, a claim about prevalence that a selected set of examples cannot support. (d) The source-tier migration of correction 29 was incomplete: the Endocrine Society guideline remained “read in primary” and §7.4 listed only primary, abstract and secondary tiers. (e) B1 placed duration of exposure inside baseline risk, conflating susceptibility with the time horizon of a cumulative difference. (f) B2’s opening described the cisgender route evidence as measuring “the acute first-pass” effect, conflating mechanism with observational outcome data. (g) Smaller: the claim map kept “no risk-positive cyproterone signal”; Manchkanti was said to have “no fuller publication”, more than a search can establish; interruption harms were stated more firmly than the survey-level evidence; smoking was listed among established VTE factors without qualification; and confounding by indication was said to bias “either way” where its expected direction is known. Caught by: fourth external review. Changed: each restated as the review recommended; the author-confirmation placeholder in statement (e) is retained; the interruption statement now cites WPATH SOC-8 on hormone therapy after gonadectomy; and Saxby 2026 (EClinicalMedicine), filed in the archive on 14 October 2026, is now read in primary.

31 · Fifth external review: omitted evidence and an exposure misdescription. Wrong: (a) The expanded Kaiser STRONG analysis (Goodman & Zhang 2021, a 2021 PCORI final research report on 3325 transfeminine hormone initiators) was absent, and with it route-, drug- and dose-specific estimates and a higher ischaemic-stroke signal. Several statements of evidence absence were therefore false: “no comparative VTE data for injectable oestradiol”, “the only trans signal is case-series arithmetic”, “Direct, no data” in the B3 grade table, “absence of comparative data verified” in the claim map, and the description of Kaiser’s route evidence as sparse uninterpreted strata. (b) Part A omitted directly relevant mechanism studies, three of them already in the author’s archive: Scheres 2021 and Bøgehave 2025 and 2026 (paired twelve-month ENIGI cohorts of 98, 270 and 251 trans women), with Lim 2020 and Bar-On 2026 at abstract level and Bouck 2023 as a hybrid review. The claim that da Cruz was the sole independent mechanistic check was wrong, and A4’s “cross-sectional/short-exposure” basis no longer described the evidence. The r8 update search for Part A was built because the v1.1 search, restricted to 2024–2026 and excluding surrogate-only studies, could not have found them. (c) Getahun’s overall-cohort estimates (HR 1.9/2.0; the eight-year risk differences) were described as estimates among people on feminising hormone therapy; that cohort was identified by transgender status, not restricted to confirmed oestrogen recipients, with hormone use outside Kaiser incompletely captured and initiation analysed separately. (d) Pyra’s progestogen signal was compressed into an MPA-driven one; Pyra analysed micronised progesterone and medroxyprogesterone acetate separately and the MPA estimate rests on one event. (e) Interpretive residue: the “appears not to front-load” heading and paragraph, the “excess appears concentrated” heading, and A.5’s title implied patterns and comparisons the text denies establishing. (f) A claim-map row attributed da Cruz’s PAI-1 and free-protein-S finding to the Amsterdam lineage. (g) The short management statements prohibited asymptomatic thrombophilia testing outright, where D.3 permits selective testing. (h) C.2 explained the comparator pattern by the cohort sitting “nearer the male reference”. (i) The independence audit contradicted the arterial summary; the transmission appendix attributed undocumented reading behaviour to other authors and miscounted its own cases; D.4’s closing sentence left its referent ambiguous; and several smaller precision items (A3’s unnamed estimand, Seal’s reconstructed event count, Saxby’s units, Manchkanti’s publication status, the ESTHER nulls, the historical correction entries’ tense, the update ordering, the “not obtained: none” line, the undefined gate labels and the AI-review disclosure) stood as the review describes. Caught by: fifth external review; (b) is a failure of the author’s own process, since the archive already held three of the omitted papers. Changed: the expanded Kaiser report integrated in B1, B2a, B3b, Part C, the grade tables, the claim map, the overlap matrix and the source tiers, as the same lineage and not a third estimate; the mechanism studies integrated in A.4 with A4 regraded Moderate and the independence claim corrected; the Kaiser exposure description corrected across the abstract, In brief, B1 and claim map; Pyra restated; the headings, claim-map row, screening wording, C.2 clause, independence summary, transmission appendix and D.4 sentence rewritten; the smaller items corrected in the body and tables; and a full-window mechanism search added to the appendix. A sixth review (correction 32) then found residual instances that this entry had reported closed.

32 · Sixth external review: a misnamed estimand, a stroke-timing overstatement, and r8 residuals. Wrong: (a) A4 attached Bøgehave 2025’s “ΔETP 113 nmol/L×min” to the oral group’s within-person rise; 113 is the adjusted between-regimen difference in change (oral minus transdermal), and the adjusted between-group comparison at twelve months was not significant. (b) The In brief and C.1 described the expanded Kaiser stroke elevation as appearing “only after about six years”; a detectable elevation against the female comparator was also present before six years (22 events; HR 1.9, 1.1–3.1), and most events fell there. (c) The independence statements on p. 7 and the da Cruz matrix row still called da Cruz the single or only non-Amsterdam mechanism check, and Bar-On’s independent prospective pilot was described but its result unused. (d) B3’s “Not claimed … no injectable estimate either way” contradicted the injectable estimates B3 now reports. (e) The expanded Kaiser report’s MI, concomitant-progesterone and follow-up-sensitivity results were not carried into Part C, B2c and B1. (f) The overlap matrix did not distinguish confirmed from possible participant overlap among the ENIGI mechanism studies, which were absent from it. (g) The effect-size rule still promised a precision grade it did not implement, and the arterial table omitted confidence intervals. (h) Smaller: the abstract-only count read seven where nine are listed; Bouck was absent from the §7.3 inventory; the Seal event count reappeared in the claim map after the prose rejected it; A2’s population wording and A4’s “largely single-centre” predated the new studies; the Scheres APC point estimate was stated as an established direction; the headline twofold range and the C.2 and Part C concordance wording needed the expanded report; the Getahun transmission note still called the 2,842 cohort “exposed”; the transmission appendix rhetoric and the “both true” phrasing overstated the cases; the mechanism search was not reproducible as printed; and the search rerun implied an identical record set from identical counts. Caught by: sixth external review; (a) is a numerical estimand error. Changed: the Bøgehave estimand corrected and the baseline imbalance stated; the stroke timing restated with the earlier-interval elevation; Bar-On integrated and every independence statement and the matrix corrected, with explicit overlap labels and rows for the ENIGI studies; B3 provenance and the dose/level grade rewritten; the expanded report’s MI, progesterone and sensitivity results added; the precision rule rewritten and the arterial table given intervals; and the smaller items corrected. The version DOI (10.5281/zenodo.23355798) was reserved during preparation of the deposit copy.

33 · Seventh external review: final consistency and publication closure. Wrong: no new scientific error; residual propagation and closure items. (a) The abstract’s Kaiser parenthesis let the status-defined exposure caveat attach to the expanded initiation estimate; each estimate now carries its own exposure definition, and the expanded cohort’s 1.8 female-comparator HR is stated. (b) An A4 sentence asserted definite ENIGI overlap where the matrix establishes only possible overlap with Scheres. (c) An earlier revision described the external adversarial review as AI-conducted; it is in fact provided by an independent human reviewer whose identity is kept confidential, and the preparation statement now says so, with the author’s own AI use (Claude, as preparation aid and internal adversarial reviewer) stated separately. (d) The front matter and correction 32 described the version DOI as deposited; it is reserved, and the record did not resolve publicly at review time. (e) Smaller: the claim-map Part A row still listed only the historical route sources; the VTE summary cells kept 1.8–2.0 where the abstract uses 1.7–2.0; the arterial grade-table heading named only male comparators; the compact arterial summary kept a blanket “concordant” label; the Methods search-boundary paragraph omitted the mechanism search; the Toorians population cell compressed 14/14/8/20 to “n=14 per arm”; the Kuijpers 10 mg subgroup read as a trial arm; “no single study measured its named domain comprehensively” and “the Toorians null treated as underpowering” overstated; and the transmission appendix opening and Case 3 heading needed softening. Caught by: seventh external review. Changed: each corrected as described; publication-status wording set to “reserved” pending the author’s confirmation that the record is published.

Updates at version 1.1 (new information or new standard)

U1 · Competing interests. §7.1 now carries Eden Openly’s standard competing-interests and funding statement (v1.8), which post-dates v1.0.

U2 · Evidence update. A documented PubMed update search (13 October 2026 UTC) and an external review identified syntheses and cohorts not captured by v1.0, several published within v1.0’s own window; they are incorporated in Parts A–D and in “Further evidence recorded at version 1.1”, with the search strings in the search appendix.

U3 · Search boundary. Restated with the v1.1 search date; a full-window mechanism search was added at r8 (14 October 2026) and is documented in the search appendix.

U4 · Full texts filed. On 13 October 2026 (UTC) the author filed full texts for most sources previously read at abstract level or not obtained. Reading them verified the historical figures (correction 24), resolved the Kozato count (Case 3), supplied the Seal denominators (and exposed an arithmetic inconsistency in its CEE figure), corrected the characterisation of Streed 2025’s contrast between recorded and no recorded therapy, added Giltay’s cyproterone-alone null, Post’s assay and imprecision, Oger’s design and thrombin-generation finding, Kelmser 2025, Campello 2026, Smith 2004 and the full positions of Skeith & Bates 2026, and identified that Li 2024’s single event is also Laspro 2025’s.

7.3 Verification statement

Primary studies, guidelines and regulatory documents — full text obtained and checked: van Zijverden 2026 · Nota 2019 · Getahun 2018 · Burgoon 2026 · da Cruz 2025 · Toorians 2003 · Schutte 2022 · Canonico/ESTHER 2007 · Vinogradova 2019 · Kuijpers 2021 · WPATH SOC-8 2022 (Chapter 12; Statements 12.13–12.15, 12.18 and the supporting text under 12.19 verified) · Pyra 2020 (outcome is composite thromboembolism) · Martinelli 2016 · Glintborg 2022 (accepted manuscript) · EMA/70255/2020 and EMA/147755/2020 · Androcur product monograph (Health Canada) · Saxby 2026 (mortality) · Saxby 2026 (mental-health treatment) · Post 2003 · Oger 2003 · Giltay 2000 · Doll 2022 · Streed 2025 · Kozato 2021 · Kelmser 2025 · Li 2024 · Herndon 2024 · Campello 2026 · Ott 2010 · Seal 2012 · Smith 2004 · Asscheman 1989 · van Kesteren 1997 · Scheres 2021 · Bøgehave 2025 · Bøgehave 2026.

Funder final research report — full text obtained and checked: Goodman & Zhang 2021 (expanded Kaiser STRONG; a PCORI final research report, not a journal article, and the same cohort lineage as Getahun 2018).

Secondary syntheses and reviews — full text obtained and checked: Totaro 2021 (meta-analysis) · van Zijverden 2024 (meta-analysis) · Baker 2021 · Cooney 2025 (systematic reviews) · Badreddine 2022 (meta-analysis) · Laspro 2025 (systematic review and cohort) · Rothman 2024 (scoping review; accepted pre-proof) · Nolan & Cheung 2021 · Skeith & Bates 2026 (narrative reviews) · ASH 2024 (used directly for management guidance — primary prophylaxis, screening and post-VTE positions — not as primary outcome evidence) and Nolan & Cheung 2024 (framing and management context; not primary outcome evidence). Bouck 2023 (hybrid review with exploratory original assay and case components; framing only, its original component not treated as a cohort). None of these is counted as an independent cohort lineage.

Complete source at its only publication level: Manchkanti 2023 (conference abstract; no fuller publication was identified as of the 13 October 2026 search).

Sources marked in bold were added or upgraded at v1.1, most from full texts filed by the author on 13 October 2026 (UTC).

Read in published abstract only (full text not obtained; flagged at every use): Balshi 2026 · Franco-Moreno 2025 (systematic review) · Huo 2024 · Federico 2025 · Saleh 2025 · Slack 2024 · Vecchiato 2026 (expert opinion) · Lim 2020 · Bar-On 2026. [9]

Read in full (current published guideline) — figure verified: Endocrine Society 2017 guideline (10.1210/jc.2017-01658, Hembree et al.) — the author’s archived copy is the correct published version (the connector’s copy was flagged superseded; the author’s read overrides that). Table 15 verifies the serum-oestradiol monitoring range (100–200 pg/mL, testosterone <50 ng/dL), framed as a feminisation/suppression target, not a VTE-safety ceiling. B3 now states the figure as verified rather than attributed.

Not obtained: no cited source was wholly unavailable. [0] Nine are held at published-abstract level and are flagged at every use, as listed above.

Claim-to-reference discipline: every numerical claim in the graded body is traced to a source read in full, or the limitation is stated in text. Figures resting on unobtained sources have been either removed (items 6, 7) or explicitly bracketed. The claim-to-reference map below verifies that each citation resolves to a source that supports the claim, not merely that the citation resolves, and is cross-referenced with the study-overlap matrix so that no figure re-cited across a single lineage is counted as independent corroboration. It was re-run against the v1.1 reference list.

Claim-to-reference map (supplementary). A standalone claim-to-reference map for the load-bearing graded-body claims (Parts A–D) is deposited with this version as a supplementary file. For each claim it records every source cited, the tier at which that source was read, its archive DOI and the result of the deposit gate. Of the 37 distinct graded-body source DOIs, 36 are held in the source archive; the one exception is the single source read in published abstract only. It was built with AI assistance against the archived copy of each source and the deposited text, and was checked and verified by the author.

AI-preparation note (cross-reference §7.4): this review was prepared with a large language model (Claude, Anthropic) used for source retrieval, arithmetic and structural editing and as an internal adversarial reviewer, and it was additionally subjected to independent external adversarial review by a human reviewer whose identity is kept confidential. Errors in this log arose in drafting, whether AI-assisted or the author’s own (items 6 and 8 among them); they were caught by external review, by the author and by post-deposit review, which is why this log exists. Every claim, number and citation is the author’s responsibility.

Author verification pass (§7.4). Every figure in the graded body was checked by the author against the best available source at the tier stated for it in this section. The v1.0 pass missed reference-level and figure-level errors later found in a post-deposit accuracy review (13 October 2026 UTC); they are recorded as corrections 18–33 and fixed in v1.1.

7.4 Preparation and authorship statement

Preparation. This review was prepared with the assistance of a large language model (Claude, Anthropic), used for source retrieval, arithmetic verification, structural editing and adversarial review. The external adversarial review drawn on during production was provided by an independent human reviewer whose identity is kept confidential; it is not a formal journal peer review, and this paper is not peer reviewed. Claude (Anthropic) was additionally used as an internal adversarial reviewer during preparation. Every claim, number and citation was checked by the author against the best available source at the tier stated for it in §7.3 — a full primary study, a full guideline, regulatory document or review, a published abstract, or, where explicitly flagged, a secondary characterisation — and the author is responsible for all of them. Several errors introduced during AI-assisted drafting are recorded in the correction log; they were identified by the author and by an external reviewer, and this is why the correction log exists.

Rationale, recorded because the alternative was considered and rejected. Omitting this statement does not remove an attack vector — it creates a better one. Silence invites the question “why didn’t she say so?”, which is the story that destroys a corpus. This corpus rests on disclosing what it cannot be trusted to hide: the competing interest, the correction log, the population flags, the “read in abstract; full text not obtained.” A standard that says declare your bias, log your errors, flag your extrapolations — and omit this one thing because it is inconvenient is a standard with a hole in it, and the hole is exactly where the author had something to lose. The statement also does necessary work: it explains why the correction log exists, converting the recorded errors from evidence of carelessness into evidence of process.

This review is a self-published Evidence Review deposited to Zenodo, not a peer-reviewed journal submission; the full-preparation disclosure above therefore applies. For peer-reviewed submission the standing commitment is different — the author writes in her own voice and the AI acts as adversarial reviewer only — and that distinction is declared accurately per venue.

7.5 Correspondence record

Not applicable to this review. No discrepancies in third-party documents were formally reported to any body in the course of this review. Certain observations about secondary sources — a significant finding omitted from one review’s characterisation of a primary (the progestin–thromboembolism signal in Pyra 2020), a sample-size inconsistency within another (Kozato reported as N=402 in body text and N=407 in table of the same review; the primary’s 407 includes five patients not on hormones), and the propagation of a “45-fold (6.3%)” figure across two reviews citing a single 1989 primary, accurately but without its observed-versus-expected comparator — are recorded in the evidence-transmission appendix as part of this review’s own transparency, not reported to the authors or publishers as formal corrections. Should the author elect to raise any of these with a source’s authors or a correction channel, that would be a separate, deliberate act recorded here at that time.

Mental-health benefit — graded declaration

The benefit that counterweights the venous and arterial risks is graded here as a declaration rather than stated in the body, for two reasons: mental-health outcomes lie outside this review’s VTE / MI / ischaemic-stroke scope and are not its primary subject; and the benefit is load-bearing in any risk–benefit reading, so it is held to the same four-axis evidential standard as the harms rather than asserted narratively.

The author’s competing interest — declared in §7.1: a trans woman who supports access to gender-affirming care — bears directly on this claim. This is the finding the author would most prefer to be true. It is therefore graded at least as conservatively as the harms, and not more generously — which is the entire purpose of the symmetric-bias standard, tested here most directly.

The claim, stated plainly

Feminising gender-affirming hormone therapy is desired and clinically important to many of the people who seek it, and a systematic review of predominantly observational studies found it associated with improved quality of life and reduced depression and anxiety, rating the strength of that evidence low (Baker 2021); a 2025 systematic review reached a similar low-certainty judgement and reported no feminising-specific estimates (Cooney 2025). Evidence bearing on suicide attempts and on mortality is weaker, less consistent, and more heavily confounded — the same review could draw no conclusion on death by suicide — and must not be collapsed with symptom-scale measures into a single figure or a single claim.

Four-axis grade — the same scheme applied to the harms

Scope

A full appraisal of the mental-health and psychosocial outcomes of gender-affirming therapy — with its own source base, its own grading, and the adolescent-versus-adult distinctions those outcomes turn on — is a separate review, not this one. This declaration grades only the counterweight needed to read ER-018’s risk findings in context; it does not stand as this platform’s full position on the benefit evidence. One recent feminising-specific dataset is noted without changing the grade: an Australian whole-of-population study of 20,358 people initiating oestradiol-based therapy, using a dynamic difference-in-differences design with future recipients as controls (Saxby 2026, EClinicalMedicine; read in primary; ages 15 and over, analysed as 15–24 and 25 or older), found mental-health service and prescription use rising around initiation and declining thereafter. Five years after initiation, the estimated change relative to three years before initiation was −0.29 mental-health services per person per year (95% CI −0.60 to 0.03), which is not statistically distinguishable from baseline, and +0.53 antidepressant or anxiolytic prescriptions per person per year (0.20–0.86); reductions were concentrated in people with higher baseline engagement. Its outcome is healthcare use, not depression or quality of life, and its feminising-specific pattern is mixed, so it does not upgrade causal attribution.

What this declaration does, and does not, license

It does not convert a risk–benefit judgement into a foregone conclusion. A transgender-population association with potentially important mental-health and quality-of-life benefit, with limited causal attribution and only partly feminising-specific evidence, is precisely the kind of finding that shared decision-making exists to weigh — patient by patient — against a reproducible VTE association whose absolute and treatment-attributable magnitude varies by patient. It does not license withholding therapy on thrombotic grounds without that weighing; nor does it license disregarding thrombotic risk because the benefit is valued.

Stated once, plainly, and symmetrically: the harms in this review are graded conservatively, and so is this benefit. Neither is inflated to serve the reading the author would prefer. Withholding or interrupting desired therapy may have psychological consequences and, particularly with prolonged interruption or after gonadectomy, physical consequences (WPATH SOC-8 notes that hormone therapy after gonadectomy avoids the sequelae of hypogonadism, including osteoporosis); those effects are not quantified in this review, and they belong in the same decision as the thrombotic risk — neither privileged by where it happens to sit in this document.

Methods statement

This states how the review was produced, so a reader can judge its coverage.

This is a narrative review, not a systematic review

ER-018 is a narrative evidence review. It did not follow a registered systematic-review protocol: there was no exhaustive database search across pre-specified terms, no PRISMA flow, no independent dual screening, and no formal risk-of-bias instrument applied uniformly to every study. It therefore makes no claim to have captured all relevant evidence, and its conclusions should be read as a graded appraisal of the principal available sources, not as a complete synthesis. This disclaimer is load-bearing and travels with the deposit; it is not a hedge but an accurate description of method.

The choice is deliberate. The review’s value is in appraising the certainty of a contested literature — separating causal attribution from effect size, direct evidence from cisgender extrapolation, and independent cohorts from re-cited ones — rather than in tallying every publication. Where that appraisal depends on a source, the source is named, its status disclosed, and its independence recorded.

Source discovery

Sources were identified from: the platform’s held source archive; targeted retrieval of primary studies where a claim required them; the reference lists of the principal cohort and review papers (notably the contemporary Amsterdam analysis and the ASH education review); and references surfaced by external adversarial review. The emphasis was on locating the primary outcome cohorts in feminising hormone therapy (venous and arterial), the mechanistic studies in trans populations, and the cisgender route/molecule evidence that the trans literature leans on. Discovery was purposive, not exhaustive.

Search boundary

Version 1.0 reflected evidence available to July 2026, identified purposively and anchored by the most recent contemporary cohort analysis obtained (van Zijverden 2026). For version 1.1 a documented PubMed update search was run on 13 October 2026 (UTC), publication dates 1 January 2024 to 13 October 2026, using the strings in the search appendix; a separate full-window PubMed mechanism search was run on 14 October 2026, covering publication dates from 1990 through that day, with its exact query and 74-record result documented in the search appendix; the clinical update search returned 171 records, all screened by title and, where needed, abstract, with two sensitivity strands (MeSH-based without a hormone block, 221 records; perioperative, 15 records). The update search identified sources published within v1.0’s window that v1.0 had not captured — among them the 2024 cardiovascular meta-analysis, the 2025 VTE systematic review and an Australian mortality cohort published in February 2026 — and these are now incorporated. Two relevant sources (Balshi 2026; Cooney 2025) are not retrieved by the main string, for the reasons stated in the appendix, and were added by hand.

Study selection and appraisal

Every load-bearing numerical claim in the graded body was traced to a source and the source’s status recorded in one of four tiers: read in full (full text obtained and checked; “read in primary” is reserved for primary studies, and reviews, guidelines and regulatory documents are “read in full”), read in abstract only (flagged at every use), held but retrieval-limited, or not obtained (cited via a secondary source or the pooling meta-analysis, and flagged as an open gate). The verification statement lists every source by tier.

Two rules governed appraisal:

• Primary outcome grades rest on primary studies. The cardiovascular outcome grades are based on primary studies wherever available; secondary syntheses are not substituted for primary outcome data. Secondary syntheses are also used directly where the object being graded is itself a synthesis-level conclusion: Baker 2021 and Cooney 2025 support the out-of-scope mental-health declaration, and ASH 2024 supplies expert management positions in Part D. These uses are identified as secondary or expert synthesis, not as primary outcome evidence. Systematic-review pooled estimates (van Zijverden 2024, Franco-Moreno 2025, Badreddine 2022, Totaro 2021) are reported as synthesis-level results, with their eligibility, overlap and pooling limitations distinguished from primary-study estimates; they inform context and the independence audit, not the principal cohort grades. Narrative reviews and expert syntheses supply clinical framing or explicitly attributed management positions. No synthesis is counted as an additional independent cohort. No figure in the graded body now rests on a secondary characterisation of an unobtained primary. Gate labels carried from drafting and used in the provenance notes are: G1 ethinylestradiol exposure, G3 population directness, G4 absolute-versus-relative framing, G6 venous–arterial separation, G7 cohort independence.
• Overlapping cohorts were identified before figures were compared. A study-overlap matrix maps which cohorts are independent, which share an institutional lineage, and which meta-analysis pools the others, so that numerical agreement within a single lineage is never counted as independent corroboration.

Certainty grading

ER-018 uses a four-axis editorial certainty scheme — causal attribution, observed effect size, clinical importance, population directness — as a declared exception to the platform’s house three-axis scheme, because this topic turns on distinctions the field routinely collapses. The scheme is editorial and explicitly not formal GRADE; a written decision rule anchors each axis, and the estimand is named beside every effect-size grade. The rationale and the rule are stated in the certainty-scheme note.

Adversarial review and bias handling

The review was produced under iterative external adversarial review, with a symmetric bias standard as its explicit discipline: over-claiming benefit is treated as the same error as over-claiming harm, and reassuring findings are held to the same scrutiny as alarming ones. The author’s competing interest is declared before the findings (declarations block). The correction record documents the substantive errors identified during production and their sources; it is retained as evidence of method, not removed.

Preparation

The review was prepared with the assistance of a large language model used for source retrieval, arithmetic verification, structural editing and adversarial review. Every claim, number and citation is the author’s responsibility; errors introduced during AI-assisted drafting are recorded in the correction log. The full preparation and authorship statement is in the declarations block (§7.4).

What this method does not deliver

A reader should not infer from any conclusion here that the underlying evidence base is complete, systematically searched, or free of publication and ascertainment bias. Where the evidence is thin, the review grades it thin; where a source could not be obtained, it says so; where a figure rests on one re-cited dataset, the overlap matrix shows it. The method’s honesty is in its disclosure, not in a completeness it does not claim.

Part A — Coagulation mechanism

Certainty at a glance (four-axis — see the certainty-scheme note)

Editorial certainty judgements, not formal GRADE ratings.

A.1 — The premise: first pass

Oral oestrogen reaches the liver through the portal circulation before systemic distribution, producing greater first-pass hepatic exposure than non-oral administration. This alters the synthesis and regulation of multiple proteins across the coagulant, anticoagulant and fibrinolytic systems — some rising, some falling — with the pattern and magnitude varying by oestrogen, dose and regimen rather than moving in one uniform direction. Transdermal and injectable routes avoid that gastrointestinal first pass; transmucosal (sublingual or buccal) dosing can partially bypass it through absorption across the oral mucosa, though a swallowed fraction may still undergo gastrointestinal and hepatic first-pass metabolism. In each case the liver still meets circulating oestradiol and its metabolites, but not the concentrated portal bolus — and sublingual dosing produces sharp early peaks that differ from steady-state transdermal or depot delivery, a pharmacokinetic point Part B3 takes up. In postmenopausal women, randomised trials show the direction directly: oral 17β-oestradiol induced ETP-based activated-protein-C resistance against both placebo and transdermal oestradiol, while transdermal did not differ from placebo, and only the oral arm raised prothrombin fragment 1+2, a marker of thrombin generation (Oger 2003; double-blind, 196 women randomised to oral 1 mg or transdermal 50 µg 17β-oestradiol, each with micronised progesterone, or placebo; per-protocol analysis of 160, intention-to-treat similar; the APTT-based assay showed no effect in any arm; read in primary); a double-blind placebo-controlled trial using the same ETP-based assay found significantly larger increases with oral (+102.7%) than transdermal (+26.9%) oestradiol, the transdermal rise reaching significance only at cycle 13 and not over the study period as a whole (ANCOVA versus placebo P = 0.07), and the oral rise not fully reversed four cycles after stopping (Post 2003; 152 women; read in primary). Both are read in primary, are cisgender and menopausal, and use doses below feminising regimens, so they establish the direction of the route effect, not its size in transfeminine care — and Post’s imprecise transdermal rise means transdermal oestradiol is not demonstrated to be haemostatically neutral, though neither is that rise firmly established. The route question, stripped to its mechanism, is therefore less about skin versus tablet than about how much oestrogen the liver is made to process — and, as the rest of Part A argues, which oestrogen and at what dose, on evidence unevenly distributed and weighted to one centre.

A.2 — What actually moves: the haemostatic shift, measured in trans people

The shift can be measured directly in this population, on the particular markers each study chose.

Toorians and colleagues measured acquired activated-protein-C resistance — a haemostatic phenotype associated with venous thrombosis in other populations, though not validated as an individual predictor in transfeminine care — with the natural anticoagulants, across four regimens (Toorians 2003; n = 14/14/8/20; VU University Medical Center, Amsterdam; four-month within-person design for three arms — the oral-oestradiol arm had no baseline and was compared with pooled baselines; markers, not events). On oral ethinylestradiol with cyproterone the normalised APC-sensitivity ratio rose from 1.2 to 4.1 — a resistance that, as a laboratory value, falls in the range the assay records for factor V Leiden carriers, though the comparison is one of laboratory magnitude only and implies nothing about equivalent absolute risk, biology or persistence. Total and free protein S fell about 30%; protein C rose 9%. Cyproterone alone was associated with a small increase in this APC-resistance assay (1.4→1.8) — a measurable haemostatic effect in this sample, whose clinical VTE significance is unknown, and which Part D takes up. That no thrombosis occurred is a statement about size and duration — four months across small arms has insufficient power to detect an event of this rarity — not about safety.

da Cruz and colleagues measured a different panel (da Cruz 2025; n = 40, median 36.5 months, 65% oral oestradiol valerate; matched cisgender women and men; Porto Alegre — independent of Amsterdam; cross-sectional): PAI-1 higher and free protein S lower than in cisgender men, while antithrombin, protein C, prothrombin time, thrombin time, VCAM-1 and fibrinogen did not differ. These findings point in directions conventionally associated with reduced fibrinolysis and reduced anticoagulant activity respectively, while the remainder of the measured panel did not differ. SHBG tracked inversely with free protein S — consistent with hepatic oestrogenic exposure, but not specific to route, dose or a causal haemostatic pathway (SHBG being a marker of exposure, not a validated individual predictor).

A.3 — The ethinylestradiol comparison: large, but molecule and dose are entangled

Oral 17β-oestradiol, which shares the hepatic first pass with oral ethinylestradiol, produced an APC-resistance ratio no different from transdermal oestradiol or cyproterone alone, and no statistically detectable difference on protein C, protein S or prothrombin — while the ethinylestradiol arm moved sharply. High-dose ethinylestradiol thus produced substantially greater haemostatic change than the studied 17β-oestradiol regimens; but the design cannot isolate molecular structure from dose, because the ethinylestradiol was given at a single dose of 100 µg (the authors suggest a dose relationship by comparison with 30 µg contraceptive doses; none was tested), and molecule and dose are confounded here. Toorians and colleagues themselves attribute the ethinylestradiol effect to its molecular structure rather than to the hepatic first pass the two oral oestrogens share; ER-018 holds that interpretation at arm’s length because a single EE dose cannot separate structure from dose. The finding’s principal relevance is to historical exposure and to continuing unsupervised ethinylestradiol use — which da Cruz notes still occurs, often at high doses — not to contemporary prescribed oestradiol.

Two limits keep this honest. The fibrinolytic axis moves with regimen even where APC resistance is unmoved: oral ethinylestradiol with cyproterone, but not transdermal 17β-oestradiol with cyproterone, lowered tissue-plasminogen-activator and PAI-1 antigen (tPA 7.9 → 3.8 ng/mL and PAI-1 25.7 → 8.9 ng/mL, both P < 0.001; transdermal arm P = 0.45 and 0.91), which the authors attribute to increased hepatic clearance with endothelial tPA release unchanged (Giltay 2000; randomised between the two oestrogen arms, 15 per arm, with non-randomised cyproterone-alone and testosterone groups; read in primary) — a contrast that, like Toorians’, confounds route with molecule, is not cleanly prothrombotic, and sits beside fibrinolytic markers that are inconsistent across the trans studies. And Part A characterises only ethinylestradiol against 17β-oestradiol; it does not characterise conjugated equine oestrogen, whose elevated risk is so far an epidemiological association (Part B) that cannot substitute for direct mechanistic evidence.

A.4 — The contemporary picture: heterogeneous, not “mild”

Studies of haemostatic markers during contemporary feminising therapy do not support a single characterisation such as “mild.” Findings depend on regimen, comparator, exposure duration and endpoints. Studies of coagulation and anticoagulant variables have generally found smaller changes with 17β-oestradiol than with high-dose ethinylestradiol; da Cruz found the parameters measured broadly similar to cisgender women. By contrast, Schutte found increased platelet-activation markers after twelve months of transdermal oestradiol plus cyproterone acetate (PF-4 +17%, β-thromboglobulin +13%), with a transient fibrinogen rise; the study could not separate oestradiol from cyproterone, and PAI-1 did not clearly change. Larger paired cohorts sharpen this. In 98 trans women measured before and after twelve months of oestradiol with cyproterone (Scheres 2021; ENIGI, Amsterdam; read in primary), factors IX and XI rose (+9.6 and +13.5 IU/dL) and protein C fell (−7.7 IU/dL); the APTT-based APC-ratio change had an anticoagulant-direction point estimate whose interval included no change (+0.15, −0.01 to 0.31), and route changed the pattern rather than its presence. Lower values in that APTT-based assay mean greater resistance, the opposite convention to the ETP-based measure in Toorians, so the two are not directly comparable. In 270 trans women (Bøgehave 2025; ENIGI, Amsterdam and Ghent; read in primary) endogenous thrombin potential rose after both oral and transdermal oestradiol with cyproterone (within-group change 259 nmol/L×min, 95% CI 217–300, oral; 114, 64–164, transdermal). The adjusted increase was greater in the oral group by 113 nmol/L×min (20–205; P = .011) — a between-regimen difference in change, not the oral group’s own rise — while the adjusted between-group comparison at twelve months was not statistically significant, and route assignment was observational, with the transdermal group older (median 38 against 23 years) and higher at baseline (1589 against 1308); in 251 (Bøgehave 2026; read in primary) clot formation increased and clot lysis decreased, again most with oral. The two Bøgehave analyses use overlapping samples from the same ENIGI cohort; participant overlap with Scheres is possible but not quantified here, and all share part of the Amsterdam recruitment setting and clinical practice. Independently, a cross-sectional Australian study of 26 trans women (16 oral, 10 transdermal) found hypercoagulable global-assay parameters against cisgender men alongside increased overall fibrinolytic potential, and no detectable difference between routes (Lim 2020; abstract-level). An independent Israeli prospective pilot reported different six-month laboratory patterns with oral oestradiol plus cyproterone and with divided-dose sublingual oestradiol monotherapy (Bar-On 2026; 30 treatment-naïve participants; abstract-level): free protein S fell more with the sublingual regimen, and other assay findings differed by endpoint. Route, anti-androgen use and dosing schedule are confounded there, so no route effect or safety conclusion follows. Fibrinolysis findings across studies remain inconsistent. Together these indicate a heterogeneous, endpoint-dependent response rather than a uniformly mild or uniformly procoagulant effect, and no assay panel covers every component of haemostasis, nor are these laboratory measures validated here as individual clinical-VTE predictors or as mediators of a quantified share of the cohort association. da Cruz’s own register is the correct one: not safety, but “some reassurance,” beside a cross-sectional design, small sample, regimen heterogeneity and no older participants — and, as ER-018 adds, no clinical endpoint, in a cohort that was 92.5% oral and 27.5% on conjugated equine oestrogen.

A.5 — The hinge: mechanistic findings and clinical associations, and the unresolved link

The mechanistic and epidemiological evidence are not directionally discordant in any simple sense. Some contemporary-regimen studies identify modest procoagulant changes — increased platelet-activation markers, changes in selected coagulation or anticoagulant proteins — while other domains appear minimally altered, transiently altered, or shifted toward cisgender-female values. What cannot be said is that the mechanism agrees with the epidemiology: some surrogate findings point in the same prothrombotic direction as the clinical signal, but the mechanistic literature is heterogeneous across domains, regimens, sampling times and designs, and does not speak with one voice.

The central uncertainty is not merely whether a procoagulant signal exists, but whether these heterogeneous surrogate changes are causally related to — and quantitatively sufficient to explain — the relative VTE associations reported in observational cohorts (Part B). That question cannot be answered by setting a 13–17% marker change beside an incidence ratio: the two are not commensurable, and the mismatch is not itself evidence of unexplained residual risk. Nor are these markers validated as mediators of clinical VTE in transfeminine care; they are associations with selected haemostatic variables, not demonstrated causes of a given share of events.

Historical ethinylestradiol exposure, dose and route, antiandrogen co-treatment, population differences and residual confounding all bear on any remaining gap, which Part B adjudicates. The mechanism is not the verdict; it is the set of constraints within which the epidemiology must be read.

Provenance and verification (Part A)

• Read in primary: Toorians 2003 (10.1210/jc.2003-030520); da Cruz 2025 (10.1371/journal.pone.0323606); Schutte 2022 (10.1371/journal.pone.0261312).
• Read in primary (v1.1): Giltay 2000 (10.1161/01.atv.20.5.1396) — fibrinolysis; supports a hepatic-clearance mechanism for oral ethinylestradiol; cyproterone alone did not change tPA or PAI-1. Post 2003 (10.1161/01.ATV.0000074146.36646.C8). Oger 2003 (10.1161/01.ATV.0000087141.05044.1F).
• Read in primary (v1.1 r8): Scheres 2021 (10.1111/jth.15256); Bøgehave 2025 (10.1016/j.jtha.2025.03.006); Bøgehave 2026 (10.1016/j.rpth.2026.106648) — paired twelve-month ENIGI cohorts, filed in the archive before v1.1 and missed by Part A until the fifth external review. Bouck 2023 (10.1016/j.rpth.2023.102197) is a hybrid review with illustrative cases and exploratory assay data; it is used for framing only, and its case and assay components are not treated as cohort evidence. Abstract-level: Lim 2020 (10.1210/clinem/dgaa262); Bar-On 2026 (10.1055/a-2945-4864) — a non-randomised six-month comparison of oral oestradiol with cyproterone against divided-dose sublingual oestradiol monotherapy in 30 treatment-naïve trans women, which confounds route with anti-androgen and dosing schedule and cannot isolate a sublingual route effect.
• Centre lineage (G7): Toorians, Giltay, Schutte are the Amsterdam gender-clinic lineage (VUmc/Amsterdam UMC); limited external replication from a single centre, not demonstrated participant overlap. Bøgehave 2025 and 2026 analyse overlapping samples from the same ENIGI cohort, which the 2026 paper states, and are not independent replications of each other. Scheres uses Amsterdam ENIGI samples collected August 2012 to September 2015, inside the Bøgehave studies’ April 2012 to March 2020 recruitment window: participant overlap is possible but its extent is not established here, and shared institution and clinical practice create dependence even where participant identity is unknown. The Ghent component is another recruitment setting, not a wholly independent replication. The independent mechanism sources are da Cruz (Porto Alegre) and Lim (Melbourne), both cross-sectional, and Bar-On (Tel Aviv), a small prospective pilot; Lim and Bar-On are appraised at abstract level.
• Not claimed: no individual SHBG or hepatic-responder stratification; no clinical-safety claim from markers; no integrated prothrombotic verdict from two markers; the Toorians non-significant comparisons interpreted with their small samples and design limitations, clinically relevant differences not excluded.

Part B — Venous risk: magnitude, route and molecule

Scope of Part B

Part B grades the epidemiological evidence for venous thromboembolism in feminising therapy on the axis molecule × route × population. Five outcomes: (1) VTE overall; (2) route; (3) molecule; (4) dose/level; (5) injectable. Arterial events are Part C (G6); risk modifiers Part D; absolute-versus-relative framing within each outcome.

B1 — Venous thromboembolism, overall

Four-axis grade

Editorial certainty judgements, not formal GRADE ratings.

An exposure-defined estimate from the same Kaiser lineage

The expanded Kaiser STRONG analysis (Goodman & Zhang 2021; PCORI final research report, read in full) followed 3325 transfeminine participants who initiated hormone therapy at two California sites between 2006 and 2020, matched ten to one with cisgender referents. It found 44 VTE events, an incidence of 3.9 per 1000 person-years, and adjusted hazard ratios of 1.7 (1.1–2.4) against cisgender men and 1.8 (1.3–2.6) against cisgender women, with estimates further from the null after about two years of follow-up (1.8 and 2.1). Because entry is defined by starting therapy rather than by transgender status, it partly answers the exposure-definition problem below — but it is the same Kaiser lineage as Getahun and overlaps it, so it is corroboration within a lineage, not a third independent estimate, and it is a funder’s final research report rather than a journal article. Its VTE results are also sensitive to follow-up handling: censoring after a disenrolment gap of more than ninety days attenuated the hazard ratios to 1.4 (0.9–2.1) against men and 1.6 (1.1–2.5) against women, while the stroke elevation persisted. That does not reverse the direction of the evidence, but it adds uncertainty about magnitude and outcome capture.

The absolute picture first (G4)

Lead with the matched, adjusted comparisons rather than a generic background rate. In the Kaiser STRONG cohort’s overall transfeminine cohort — identified by transgender status, not restricted to confirmed oestrogen recipients — adjusted VTE risk differences against matched cisgender controls were 4.1 per 1000 at two years and 16.7 per 1000 at eight years versus cisgender men (95% CI 1.6–6.7 and 6.4–27.5), and 3.4 (1.1–5.6) and 13.7 (4.1–22.7) versus cisgender women. These are overall-cohort differences, not the absolute effect of starting contemporary oestradiol. Crude incidence was 5.5 per 1000 person-years in STRONG and approximately 2.4 per 1000 in the later Amsterdam registry analysis — but these two crude rates are not directly comparable without age and design standardisation (the populations, calendar periods, age structures, outcome capture and treatment histories all differ), and the lower Amsterdam rate is not in itself evidence of a smaller treatment effect. A frequently-quoted young-adult background near 1 per 10 000 per year is not age-matched to these cohorts and should not anchor the contrast. Two pooled/crude proportions circulate — a meta-analytic 2.0% (with very high heterogeneity, I² 89%) and a contemporary single-centre 1.4% — but prevalence is not incidence, the 2% pools Getahun, Nota and van Kesteren rather than corroborating them, and the 1.4% is a crude proportion over variable follow-up its authors warn against reading as a rate.

The relative picture — numerical concordance, not a settled effect

A 2026 Amsterdam registry-linked analysis (van Zijverden), observing events from 2012 to 2022 and adjusting standardised incidence ratios for age, sex, calendar year and socioeconomic status, estimated a VTE SIR of 1.81 (1.33–2.35) versus general-population men and 1.74 (1.28–2.26) versus women. This is the most recent estimate from this cohort lineage and should take precedence for contemporary event ascertainment; the 2019 Amsterdam analysis (Nota, SIR 4.55/5.52) remains relevant as an earlier analysis with a different reference population (which van Zijverden describes as a Norwegian control cohort), different outcome capture (medical records for the trans cohort, registry data for controls), and the ethinylestradiol era, not as void. Kaiser’s adjusted hazard ratios were 1.9 (1.4–2.7) versus men and 2.0 (1.4–2.8) versus women.

These strongest contemporary estimates are numerically similar — near 1.8–2.0 — but they are not the same quantity: an individually-adjusted hazard ratio from a matched insured US cohort, and an SES-adjusted standardised incidence ratio against national rates from a Dutch clinical cohort. Nor are they equally adjusted: Kaiser controlled at the individual level for smoking, BMI, blood pressure and cholesterol; van Zijverden adjusted its SIRs for age, sex, calendar year and SES but could not adjust for lifestyle, which it compared only descriptively in a small subset (174 trans women). So the apparent twofold-versus-fivefold conflict is resolved — but what replaces it is approximate numerical concordance across different comparators, estimands and adjustment sets, which is informative and should not be presented as a settled pooled effect or a stable biological magnitude.

Several factors could contribute to the higher historical estimates — greater historical ethinylestradiol exposure, calendar period, comparator construction, adjustment, outcome ascertainment and survivor selection — and their individual contributions cannot be separated from the available analyses. Two can be partly examined. Ethinylestradiol (G1, partly addressed): Nota’s exclusion of pre-2001 starters dropped its VTE SIR from 5.52 to 3.92 (women) and 4.55 to 3.39 (men) — a treatment-era sensitivity analysis, imperfect but direct. van Zijverden’s 2012–2022 event window post-dates routine Dutch EE prescribing, so current EE exposure is unlikely; but the cohort initiated GAHT from 1972, van Zijverden performed no past-EE sensitivity analysis (its authors note almost all pre-2001 starters had used EE), and it is therefore not an EE-naïve cohort — prior EE exposure, treatment switching and survivor selection are not excluded. G1 is thus partly addressed by Nota’s era analysis and contextually by the later window, not “discharged.” Adjustment differed between analyses (above), and may account for some of the remainder.

The honest summary: venous thromboembolism is consistently observed at higher incidence among cohorts receiving feminising hormone therapy than among several male and female reference populations, numerically near twofold in the strongest contemporary analyses. How much of that association is caused by contemporary prescribed oestradiol — rather than era, formulation, co-medication or residual confounding — remains uncertain, and no longitudinal VTE-incidence cohort provides a clean internal untreated transfeminine counterfactual to settle it. And the same detection scrutiny applied to the arterial findings in Part C applies here, though the mechanisms must be kept distinct rather than lumped: differential healthcare contact could affect diagnostic ascertainment (more frequent contact may raise the chance a symptomatic event is investigated and coded), which is separate from preventive-care differences (which would change true incidence, not its detection) and from registry under-ascertainment (which could affect either group). Their direction and magnitude here are unknown, and the concern is weaker where exposed and reference outcomes come from the same national registry — as van Zijverden notes of its own design. The point retained is only the symmetric one: whatever ascertainment scrutiny is applied to the reassuring arterial finding must be applied to the venous signal too, not reserved for the finding that does not flatter the stance.

Systematic reviews that pool these cohorts (added at v1.1)

Two systematic reviews published before v1.0 and two later narrative or expert syntheses are relevant, and each pools or restates cohorts already graded here, so none is counted as independent corroboration. A 2024 meta-analysis (van Zijverden 2024; full text, open access) estimated VTE in trans women against cisgender men at RR 2.2 (95% CI 1.1–4.5) from five studies including Getahun and Nota, with very high heterogeneity (I² 93.5%), mixed estimands treated as equivalent, and serious risk of bias in most included studies by ROBINS-I. A 2025 systematic review (Franco-Moreno 2025; abstract-level) reported thrombosis in trans women against cisgender men at OR 2.23 (1.93–2.57); the estimate rests on five of its twenty-one studies, and its pooling model, adjustment and included-study list could not be verified. Both point in the same direction as the two independent lineages; neither adds an independent lineage. Skeith & Bates 2026 (N Engl J Med; read in full) is a narrative haematology review; it restates cohorts already graded here and is not counted as corroboration, but its expert positions are cited in B2a, Part C and D.3–D.5. A 2026 cardiovascular expert opinion (Vecchiato 2026, Eur J Prev Cardiol, published online 11 October 2026; abstract-level), whose authors include Amsterdam and Padova investigators cited here, states that feminising therapy “is associated with an increased risk of venous thromboembolism” and that “causal inference is limited by the predominance of observational studies, relatively young study populations, heterogeneous GAHT regimens, short follow-up, and the absence of randomized study evidence”. It is compatible with the grades here, adds no outcome data, and is not counted as corroboration.

Slack 2024 (Endocr Pract; abstract-level), a retrospective chart review of 2,126 transfeminine and gender-diverse adults in one US urban health system, reported a documented VTE history in 0.8% of the cohort and found that none of the exposures analysed, oestrogen use included, was associated with VTE after controlling for age, race and number of comorbidities — no statistically detectable adjusted association. Because the analysis is of documented history rather than incident events, cannot establish that exposure preceded each event, and does not estimate person-time risk, it is recorded as a non-coequal counterpoint, not an estimator of treatment effect. It does not change the grade; it is stated because it cuts against a simple treatment-attributable reading, and the symmetric standard requires inconvenient evidence to be visible in both directions.

Under the symmetric standard, one dataset that cuts the other way is recorded: the Manchkanti hospital database (conference abstract) reported lower crude proportions of deep vein thrombosis in trans women than in cisgender men (0.33% vs 0.47%) and similar venous thrombosis to cisgender women; with risk-factor exclusions, no adjustment and no person-time, it does not weigh against the adjusted cohort estimates, but it is not concordant with them.

Observed cases in older and more comorbid samples — distribution of attributable excess unknown

The observed events cluster among older and more comorbid patients, consistent with general VTE epidemiology — but this is not the same as establishing how the treatment-associated relative or attributable risk varies across strata. In the prevalence meta-analysis, series with mean age under 37.5 years or mean therapy under 53 months reported few or no events (pooled point estimates of 0%, wide intervals, low power, no individual-participant data); 37.5 years and 53 months are data-derived splits, not clinical cut-offs, and do not establish that a patient under 37.5 has near-zero risk. A contemporary cohort’s sixteen VTE cases were older (median 50, against 29 in the whole cohort) and more often carried hypertension (unadjusted OR 10.7, 95% CI 3.40–33.30), hyperlipidaemia (6.9, 2.12–21.03) and diabetes (7.2, 1.64–24.85) — estimates from sixteen events, wide and hypothesis-generating, not validated predictors. Most cases had at least one reported concurrent or pre-existing risk factor, though the study’s categories should not be equated with the standard classification of a VTE as provoked by a major transient factor.

Both disciplines, opposite in direction. The clustering is useful for counselling — it makes “numerically twofold on average” more nuanced than a flat figure. But the reading that the excess is “largely driven by established risk factors rather than GAHT” points reassuring and is held at arm’s length: it rests on sparse events without a comparator, and some of those cardiometabolic conditions may change during long-term therapy, so the cohort cannot determine whether they preceded treatment, arose independently, or partly mediated risk. The clustering pattern is plausible; the partition of the incremental GAHT-associated risk across those strata is not established.

Events during long-term follow-up; treatment-specific hazard shape uncertain

Several analyses show events continuing to occur after many years of treatment: the Kaiser initiation subgroup’s hazard was imprecise and closer to the null for two years, then higher; therapy duration predicted prevalence in the meta-analysis; the contemporary US cohort’s mean time from initiation to VTE among cases was 7.8 years and the 2026 Amsterdam median was 13.3 years from hormone start to VTE (events within the 2012–2022 window only, so left-truncated). The Kaiser initiation analyses suggest time-varying associations, but the estimates are imprecise. Mean or median treatment duration among cases, and study-level duration–prevalence associations, do not identify a biological induction period or establish a hazard shape different from cisgender hormone exposure. Each strand is confounded with age and cumulative exposure, and time to event among cases is not an incidence-time analysis.

Feeding the A.5 magnitude question

Part A asked whether modest surrogate changes can account for the clinical association. The answer from the available evidence is that they cannot be quantitatively reconciled: surrogate-marker changes may support biological plausibility, but their magnitude cannot be compared with an incidence ratio, and no mediation fraction can be inferred. What Part B adds is context, not reconciliation: the strongest contemporary estimate is numerically near twofold, and older, higher estimates differed in era, adjustment, comparator selection and event ascertainment.

Historical anchor

The historical Amsterdam cohort documents a substantially higher VTE burden during high-dose oral ethinylestradiol use, now read in both primaries. Asscheman 1989 observed 19 venous thromboses or pulmonary emboli among 303 trans women treated with oestrogen plus cyproterone acetate (6.3%; 258 of them on the clinic’s standard 100 µg ethinylestradiol with 100 mg cyproterone daily) against 0.42 expected from age-adjusted general-population male rates — the “45-fold” figure. van Kesteren 1997, an update of the same clinic population, recorded 45 such events among 816 trans women, a standardised incidence ratio of 19.56 (12.27–26.18) against the general male population — the “twentyfold” figure — and attributes the fall between the two reports to its policy, from 1989, of advising transdermal oestradiol for those over 40; all but one of its events occurred on oral oestrogens. Both are observed-versus-expected comparisons against external rates, not controlled estimates, from one institutional lineage and an obsolete regimen; they are recorded here as history and do not enter the graded body.

Provenance and verification (B1)

• Read in primary: Getahun 2018 (10.7326/M17-2785); Nota 2019 (10.1161/CIRCULATIONAHA.118.038584); van Zijverden 2026 (10.1093/eurheartj/ehaf837); Burgoon 2026 (10.3390/jcm15114166). Read in full (meta-analysis): Totaro 2021 (10.3389/fendo.2021.741866).
• Independence (G7): Getahun (Kaiser) is the independent outcomes anchor. van Zijverden takes precedence over Nota but is the same Amsterdam lineage; Totaro pools the cohorts and is never cited as independent corroboration.
• Read in primary — an independent but composite cohort: Glintborg 2022 (10.1530/EJE-22-0306) — a Danish national register cohort (2671 trans persons), genuinely independent of the Amsterdam and Kaiser lineages. Its primary outcome is a broad composite “any CVD” including medication prescriptions and milder outcomes, not a clean VTE analysis, so it is not treated as a co-equal VTE estimator. Its pure venous-diagnosis signal in trans women is a non-significant trend (incidence rate 2.31 vs 1.20 per 1000py vs control men, p=0.09; underpowered), consistent with but not corroborating the ~2× estimate. Two findings from it are used directly: gender-affirming hormone therapy did not statistically mediate the CVD excess in trans women (it did in trans men) — a caution against over-attributing the venous association to GAHT; and its authors explicitly flag surveillance bias from routine annual screening at gender clinics, which supports the ascertainment caveat above from an independent source that names it in its own cohort.
• Read in full (funder final research report, r8): Goodman & Zhang 2021 (10.25302/05.2021.AD.SS4532) — the expanded Kaiser STRONG initiation cohort; same lineage as Getahun, not a third estimate.
• Abstract-level (v1.1): Slack 2024 (10.1016/j.eprac.2024.08.014) — non-coequal counterpoint; Vecchiato 2026 (10.1093/eurjpc/zwag528) — expert opinion, not counted as corroboration.
• Ascertainment: code- and registry-based throughout; imperfect, misclassification possible.
• Not claimed: no mediation estimate; no individual age/duration threshold; no route inference from case distributions; no EE-naïve characterisation of any cohort.

B2 — Route and molecule

B1 established a reproducible association, numerically near twofold in the strongest contemporary comparisons. Cases were disproportionately observed in older and more comorbid samples, without established individual-level effect modification; events occurred throughout long-term follow-up, but existing data do not establish a distinct biological latency or a treatment-specific hazard shape. The route and molecule evidence is overwhelmingly cisgender. Its mechanistic rationale centres on hepatic first-pass effects, while the route-specific clinical outcome evidence is observational.

B2a — Route: transdermal versus oral 17β-oestradiol

Four-axis grade

The recommendation for transdermal therapy rests primarily on extrapolation from menopausal studies together with hepatic first-pass biology, rather than on direct transfeminine outcome evidence. The cisgender association is directionally consistent but not “firm” in the sense of trial evidence. ESTHER (effectively a 17β-oestradiol study — only two CEE cases) gave adjusted VTE odds ratios of 4.2 (1.5–11.6) for oral and 0.9 (0.4–2.1) for transdermal; the QResearch/CPRD analysis gave 1.27 (1.16–1.39) oral and 0.96 (0.88–1.04) transdermal. Same direction, very different magnitude. Two caveats: a confidence interval crossing one does not establish equivalence, so transdermal is better described as showing no statistically detectable increase than as “neutral”; and preferential prescribing of transdermal oestradiol to higher-risk patients could bias its observed association toward greater apparent risk; other residual confounding may operate in either direction.

For trans populations the outcome evidence is thin, but it is not absent. The expanded Kaiser STRONG analysis (Goodman & Zhang 2021; PCORI final research report, same cohort lineage as Getahun; read in full) reports route strata against matched cisgender reference cohorts: among participants who started and remained on oral oestrogen, VTE hazard ratios of 1.9 (1.1–3.5) against cisgender men and 2.5 (1.4–4.5) against cisgender women; among those who started and remained on non-oral oestrogen — patches and injections together, not transdermal alone — 1.0 (0.4–2.4) and 1.1 (0.4–2.6), on six events. Each stratum compares a route group with cisgender referents rather than the routes with each other; route was not randomised; and conditioning on remaining on a route through follow-up selects on a post-baseline characteristic. It is the most route-specific transfeminine outcome evidence available, and it points the same way as the cisgender data, but it is not a route comparison and does not establish a reduction in events. The meta-analysis has no route subgroup, and a contemporary cohort’s case route-split is a numerator without denominators. What else supports the lever is mechanism, carried forward honestly from Part A: Schutte found transdermal oestradiol plus cyproterone raised platelet-activation markers — so the regimen is not haemostatically inert, though platelet activation is not the hepatic first-pass pathway the route is meant to spare, and oestradiol cannot be separated from cyproterone. The defensible position: transdermal is a reasonable preference for higher-risk patients, graded an inference from cisgender data and mechanism, not a trans-validated reduction in events. A 2026 haematology review states that “transdermal estradiol has a better risk profile than oral estrogens” and lists it as preferred for gender-affirming therapy (Skeith & Bates 2026), but the transfeminine studies it cites report “either no VTE events or only a small number of events” and do not compare routes within one analysis, so it reinforces expert consensus without supplying route-isolating outcome evidence.

B2b — Molecule: ethinylestradiol vs conjugated equine oestrogen vs 17β-oestradiol

Four-axis grade

Ethinylestradiol is strongly implicated in the larger historical associations — Part A found substantially greater haemostatic effects with the high-dose EE regimen than with the studied 17β-oestradiol regimens, although molecule and dose could not be separated — and it is deprecated, so its relevance is to legacy-era exposure in historical cohorts and to continuing unsupervised use. Conjugated equine oestrogens are chemically distinct from 17β-oestradiol and should be analysed separately rather than grouped under a generic “oestrogen” category: cisgender data put oestrogen-only CEE at 1.49 (1.39–1.60) against 1.27 for oral oestradiol, a case–control study in which a health-plan formulary switch largely determined which oestrogen was dispensed found CEE associated with higher venous-thrombosis risk than esterified oestrogens (OR 1.78, 1.11–2.84) with a dose–response, though its comparator was not 17β-oestradiol (Smith 2004, cisgender, read in primary), and the one trans dataset that separated it (Seal) reported a higher proportion of VTE among CEE users than among those on oestradiol valerate or ethinylestradiol — a small single-centre audit with VTE secondary and unstable subgroups, whose ranking of EE below CEE is a reason to lean on it lightly (thromboembolism, type unspecified, in 4.4% of 36 CEE users, 0.6% of 163 on oestradiol valerate and 0.7% of 133 on ethinylestradiol, P = 0.026; event counts are not reported, and 4.4% is not an achievable proportion of 36, so the reported percentage and denominator do not permit a reliable reconstruction of the CEE event count, in a selected sample of 165 mammoplasty cases and 165 matched controls; read in primary). 17β-oestradiol and esters hydrolysed to oestradiol (e.g. oestradiol valerate — a prodrug, not chemically identical) are the preferred contemporary formulations, supported by indirect and mechanistic evidence as less thrombogenic than high-dose ethinylestradiol; the magnitude of any advantage over other formulations in transfeminine clinical outcomes is uncertain. High-dose EE is of substantially greater concern than contemporary oestradiol; CEE is reasonably avoided where oestradiol is available, based predominantly on indirect menopausal evidence rather than a reliable trans-specific comparison — and the review does not present EE and CEE as equally established.

B2c — The progestogen and anti-androgen bridge to Part D

Progestogens should not be treated as one thrombotic class. In ESTHER (French, cisgender, menopausal hormone therapy; read in primary), the VTE association differed by progestogen class: norpregnane derivatives were associated with higher VTE odds (OR 3.9, 95% CI 1.5–10.0), whereas micronised progesterone (0.7, 0.3–1.9) and pregnane derivatives (0.9, 0.4–2.3) showed no statistically detectable association. Cyproterone is a pregnane derivative, so ESTHER does not provide a risk-positive signal for cyproterone; and because its pregnane class is lumped (it also holds medroxyprogesterone and dydrogesterone), cisgender, menopausal and at doses unlike anti-androgen dosing, it provides no cyproterone-specific estimate applicable to transfeminine care in either direction.

Pyra 2020 provides a separate, trans-direct signal. Pyra 2020 (US cohort, 2509 trans women, 19 events, read in primary) detected no statistically significant association between thromboembolism — a composite outcome that included arterial (cerebral and precerebral) and superficial venous codes as well as VTE — and oestradiol concentration or route, but recent progestin prescription was associated with roughly threefold odds of thromboembolism (adjusted OR 2.95, 95% CI 1.02–8.57; five events among recent progestin users), with a much larger and far more imprecise estimate for medroxyprogesterone acetate that rests on a single event. The finding is fragile and must be held at arm’s length: a composite outcome that is not VTE alone, five events among progestin users, wide intervals, an observational cohort in which the progestogens were micronised progesterone and medroxyprogesterone acetate and the anti-androgen was spironolactone, not cyproterone, and possible confounding by indication. One of the five events, a superficial phlebitis, occurred in a patient who had injected heroin into the affected vein the day before. It yields nothing cyproterone-specific. The two progestogens were analysed separately, and the larger medroxyprogesterone estimate rests on a single event, so the composite progestogen association cannot be attributed to that agent. Nor is it a concordant replication of ESTHER, whose pregnane estimate — the class holding both cyproterone and medroxyprogesterone acetate — was null. It is absent from the secondary review that characterised Pyra, surfacing only in the primary.

The two studies therefore support heterogeneity between progestogens rather than a general progestogen-class VTE effect, and they do not support treating micronised progesterone, medroxyprogesterone acetate and cyproterone as one clinically interchangeable thrombotic class. Cyproterone has measurable effects on selected haemostatic markers in trans studies (Part A), but its independent contribution to clinical VTE risk has not been quantified. The expanded Kaiser report adds a sparse concomitant-progesterone stratum — four VTE events, hazard ratios 3.5 (0.9–13.5) against cisgender men and 1.5 (0.5–4.7) against cisgender women (Goodman & Zhang 2021) — which neither establishes a progesterone effect nor resolves comparative risk between progestogens, and supplies no cyproterone-specific estimate; its spironolactone and anti-androgen strata are likewise not randomised drug comparisons and say nothing about cyproterone. That an accompanying progestogen or anti-androgen should not be assumed haemostatically inert is a precautionary position, not a demonstrated risk. Part D takes cyproterone up on trans-relevant grounds, principally dose and meningioma.

Provenance and verification (B2)

• Read in primary: ESTHER 2007 (10.1161/CIRCULATIONAHA.106.642280); Vinogradova 2019; Toorians 2003 and Schutte 2022 (Part A).
• Read in primary (v1.1): Seal 2012 (10.1210/jc.2012-2030) — denominators 36/163/133; counts not reported; CEE percentage arithmetically inconsistent; used with weaknesses stated. Smith 2004 (10.1001/jama.292.13.1581) — cisgender CEE strand.
• Population directness (G3): the load-bearing route and CEE evidence is cisgender; flagged throughout; differences in population, dose, regimen and study design are the standing caution against straight-across reading.

B3 — Dose, serum level, and injectable oestradiol

Two outcomes graded not established — in both directions.

Four-axis grade

B3a — Dose and serum oestradiol level

No trans study establishes a dose- or level-response for VTE. In Kaiser the maximum daily oral oestradiol dose in those with a VTE or stroke rose from 3.6 mg in the first two years to 5.6 mg after, flat in the event-free (n = 11 with events; the authors performed no statistical comparison) — untested for want of events, and entangled with duration. The expanded Kaiser report adds starting-dose strata for oral oestradiol (Goodman & Zhang 2021): among those who remained on it, VTE hazard ratios against cisgender men were 1.6 (0.7–3.6) for a starting dose of 2 mg/day or less and 3.3 (1.0–10.8) above it, but the pattern differs by comparator and by whether participants remained on oral therapy, and the ischaemic-stroke pattern ran the other way; these exploratory strata of six to sixteen events do not establish a dose–VTE relationship. The contemporary cohort had serum oestradiol for none of its cases. The Endocrine Society’s 2017 guideline suggests (a weak, grade-2 recommendation) monitoring, and its Table 15 specifies serum oestradiol of 100–200 pg/mL and testosterone below 50 ng/dL as monitoring targets, within a section that also emphasises “avoiding supraphysiologic doses or blood levels of estrogen that may lead to increased risk for thromboembolic disease, liver dysfunction, and hypertension” (Hembree 2017). The 100–200 pg/mL target is not a validated VTE threshold or a universally applicable pharmacokinetic safety ceiling. The guideline also warns that oestradiol measurement “can be very challenging” and advises laboratories participating in external quality control; any target is therefore only meaningful with the pharmacokinetic timing specified, which matters most for injectable and sublingual regimens: sublingual dosing produces a sharp early peak followed by rapid decline, and injectable regimens vary by ester and interval, so peak, midpoint and trough answer different questions and a trough alone can conceal wide peak-to-trough variability. The sampling time relative to the dose must be recorded; a pre-dose trough can help assess minimum exposure, while peak or midpoint sampling may be needed where excessive fluctuation is suspected. No sampling point is validated as a VTE-safety threshold, and the peak magnitude of sublingual dosing depends strongly on dose, assay and timing, so no single numerical peak is generalised here. The one trans-specific study (Doll 2022; read in primary; ten trans women, fixed-sequence oral-then-sublingual single 1 mg doses after a one-week washout) found sublingual oestradiol peaked at one hour at 144 ± 90 pg/mL by LC-MS/MS against an oral peak of 35 ± 8 pg/mL at eight hours; sampling in both arms ran only to eight hours, which the authors state probably underestimates the oral exposure, the wide inter-individual variation at peak is itself a reason no single figure generalises, and it was a pharmacokinetic study that excluded anyone with prior thromboembolism and reported no thrombotic outcomes. Its authors stress interpreting levels “in the context of the timing of the last dose”. Pyra 2020 (2029 trans women with hormone concentrations, read in primary) detected no statistically significant association between thromboembolism (a composite including arterial and superficial venous codes) and oestradiol or testosterone concentration in any model (oestradiol odds ratio 0.99 per 100-unit change); with fifteen events in that analysis, clinically important effects cannot be ruled out. Avoiding unnecessarily supraphysiological exposure is guideline-concordant general safety practice; no serum oestradiol concentration has been validated as a VTE-prevention target in transfeminine care (Nolan & Cheung 2021, read in full; narrative review: the concentration that feminises “without increasing the risk of complications (thromboembolic disease, cholelithiasis) remains unknown”), and the venous dose–response in trans people is unestablished.

B3b — Injectable oestradiol

Sparse comparative observational data exist for injectable oestradiol. The expanded Kaiser STRONG analysis (Goodman & Zhang 2021; a PCORI final research report, not a journal article; the same cohort lineage as Getahun, so not an independent replication; read in full) reports injectable-specific estimates against matched cisgender reference cohorts: among participants who started on injectable oestradiol, three VTE events, hazard ratio 1.7 (0.4–6.5) against cisgender men and 1.8 (0.4–7.5) against cisgender women; among those who also remained on it, two events, 3.5 (0.4–34.5) and 2.2 (0.3–14.4). Each stratum holds two or three events, the intervals are extremely wide, and the report records that two injectable-versus-male models did not converge when stratified by event history and are presented without that variable. Its ischaemic-stroke estimates in the same strata are larger and no more stable — four events, 9.7 (1.1–85.3) against cisgender men among starters and 13.9 (1.0–194.1) among those who remained — and are taken up in Part C. These data do not establish the causal effect of injection, a reliable comparison between routes, or a dose or peak-concentration threshold: injectable VTE risk is uncertain rather than unstudied. The injectable scoping review (Rothman 2024; read from the accepted pre-proof) concerns dose and serum levels and was not designed to assess thrombosis; it cites thromboembolic risk as a motivating concern, and of its included studies one reported a single deep vein thrombosis and one reported no venous thromboembolic events. Its authors judge guideline starting doses likely too high. Injectable regimens can produce high peak concentrations — particularly with larger doses or longer intervals — but a transient measured peak is not cumulative exposure, no peak-to-VTE threshold is established, and the concern inherits the unestablished level–VTE link of outcome 4. The other trans signal is case-series arithmetic: three of a contemporary cohort’s sixteen VTE cases, and two of its six unprovoked cases, were on intramuscular oestradiol — numerators without denominators (Burgoon 2026) — with the single deep vein thrombosis in a study included by Rothman 2024 the only other. The grade is symmetric — not shown to raise VTE risk, not shown not to.

Provenance and verification (B3)

• Read in full: ASH 2024 (10.1182/hematology.2024000592, secondary review — used directly for management guidance; not treated as primary outcome evidence). Getahun/Burgoon dose observations from B1.
• Read in primary: Pyra 2020 (10.1089/trgh.2019.0061) — outcome is composite thromboembolism, not VTE alone. Read in primary (v1.1): Doll 2022. Read in full (funder final research report, r8): Goodman & Zhang 2021 — injectable and starting-dose strata. Read in full (v1.1; reviews): Nolan & Cheung 2021 (narrative review); Rothman 2024 (scoping review; accepted pre-proof; final pagination from Crossref).
• Not established: a causal injectable-route effect; a reliable comparison with other routes; a dose–VTE relationship; a serum or peak-concentration threshold. Sparse injectable-specific external-comparator estimates are reported above and establish neither excess risk nor equivalence. The guideline’s 100–200 pg/mL target is a monitoring target, not a VTE ceiling, and is only interpretable with sampling timing and assay specified.

Part C — Arterial risk

Part C grades the two arterial outcomes separately from venous thromboembolism (G6). The separation is substantive: arterial events have different dominant mechanisms — atherosclerosis, plaque disruption, platelet-rich arterial thrombosis, cardioembolism and small-vessel disease — and although haemostatic pathways overlap between venous and arterial disease, the biomarker findings of Part A cannot be assumed to predict stroke or myocardial infarction. The informative comparator also shifts toward the male reference population.

The interpretive core — observed incidence, not a demonstrated effect

On the most recent registry data, arterial-event incidence in transfeminine people is not higher, and for myocardial infarction is lower, than age-, sex-, calendar-year- and SES-standardised general-population male reference rates. The 2026 Amsterdam analysis (van Zijverden), using sex-specific general-population reference rates stratified by age and calendar year and adjusted for socioeconomic status, found — in trans women versus general-population men — a myocardial-infarction SIR of 0.50 (0.32–0.71) and an ischaemic cerebrovascular-accident SIR of 0.94 (0.72–1.19). These are comparator findings: observed events against expected general-population male rates. They do not establish that gender-affirming hormone therapy prevents myocardial infarction. The study did not randomise oestrogen, had no internal untreated trans comparator, and could not adjust individual lifestyle (its lifestyle data were descriptive, in 174 of 2714 trans women); its authors themselves flag residual confounding and several alternative explanations.

The study’s authors hypothesised that the pattern reflects hormone-associated shifts in cardiovascular risk factors — feminising therapy aligning risk with the phenotypic hormone profile rather than reversing sex differences. That is biologically plausible and worth stating, but it is a hypothesis, not a demonstrated mediation, and ER-018 reports it as the authors’ interpretation rather than adopting it. Potential hormonal contributors include suppression of endogenous testosterone, exogenous oestradiol exposure and co-medications, and the available data do not separate or rank their contributions; oestradiol’s cardiometabolic changes are themselves mixed — some favourable lipid movement, possible triglyceride and body-fat increases, and inconsistent blood-pressure effects that may vary by route, dose, baseline physiology and co-medication. Whether any of these mediates the observed MI pattern is unknown.

Four-axis grade

Editorial certainty judgements, not formal GRADE ratings. The incidence column reports comparator associations; it is not a treatment-effect estimate.

C.1 — Ischaemic stroke

Two of the adjusted estimates show no detectable stroke excess against male reference populations (general-population men in Amsterdam; matched cisgender men in Kaiser): 0.94 (0.72–1.19) in the SES-adjusted 2026 Amsterdam analysis and 1.2 (0.9–1.7, not significant) in Kaiser. The expanded Kaiser analysis is less reassuring and must be stated beside them: in an initiation cohort of 3325 transfeminine participants who began hormone therapy between 2006 and 2020 (Goodman & Zhang 2021; PCORI final research report, the same Kaiser lineage as Getahun, so not independent of it), ischaemic-stroke incidence was higher than in matched cisgender reference cohorts — 33 events, adjusted hazard ratio 2.0 (1.3–3.0) against cisgender men and 2.3 (1.5–3.5) against cisgender women — with larger hazard ratios in the later follow-up interval (after six years: 11 events; 3.9, 1.8–8.6 and 4.2, 1.9–9.2). An elevation was also present in the earlier interval against the female comparator (before six years: 22 events; 1.6, 1.0–2.6 against men and 1.9, 1.1–3.1 against women), and most events by count fell there. The report found no violation of proportional hazards and split the intervals to check consistency with the earlier publication, so these exploratory interval estimates do not establish a six-year induction period or allocate the treatment-attributable excess. Within that cohort the largest stroke estimates were in the stratum that started and remained on non-oral oestrogen (13 events; 2.8, 1.4–5.6 and 4.1, 1.9–8.7), and the injectable-specific estimates are extreme and unstable (B3b). This is an exposure-defined initiation cohort rather than a cohort identified by transgender status, which is a strength; but the strata are small, the comparison is with external cisgender referents rather than between routes, and a funder’s final report is not a journal publication. The honest reading is that the stroke evidence is mixed rather than reassuring. The earlier Amsterdam figure of 1.80 against men (Nota) takes second place — it was age-adjusted only, not adjusted for smoking in a cohort with a smoking prevalence of 43–46%, used a broader stroke definition (ischaemic and haemorrhagic stroke, transient ischaemic attack and subarachnoid haemorrhage) than van Zijverden’s ischaemic cerebrovascular accident, and spanned the ethinylestradiol era. Rates lie closer to the male than the female reference population in some analyses (van Zijverden 1.20 vs women, not significant; Kaiser 1.9); these are between-population comparisons and do not demonstrate an individual longitudinal shift caused by treatment.

Three qualifiers. The 2024 meta-analysis (van Zijverden 2024) put stroke in trans women against cisgender men at RR 1.3 (1.0–1.8; six studies, I² 59.6%, serious risk of bias) and myocardial infarction at RR 1.0 (0.8–1.2), pooling Getahun, Nota and others; it is not independent of the cohorts above, but it means the broader evidence is not uniformly reassuring for stroke. In the original 2018 Kaiser analysis, the oestrogen-initiation subgroup’s stroke elevation was most evident after roughly six years — imprecise, but a reason for long-term vigilance rather than complacency. And a large US multi-institution database (Manchkanti 2023; conference abstract, no fuller publication identified as of the 13 October 2026 search, read from source) reported lower crude proportions of cerebral infarction in oestrogen-treated trans women than in cisgender men (0.21% vs 0.49%) and cisgender women (0.21% vs 0.42%), and lower myocardial infarction than in cisgender men (0.14% vs 0.38%) — directionally concordant, but held at arm’s length: administrative data excluding people with recorded risk factors, without adjustment, matching or person-time denominators. A 2026 haematology review, drawing on the same meta-analysis, describes “a possible signal indicating an increased risk of arterial events in transfeminine persons” while noting that “high-quality data are lacking” (Skeith & Bates 2026), and a 2026 cardiovascular expert opinion cautions that population-level cardiovascular disparities in transgender people “should not be attributed to GAHT alone” (Vecchiato 2026; abstract-level). The stroke evidence does not establish an oestrogen-driven excess, while leaving a long-term contribution unexcluded.

One analysis now contrasts trans people with and without recorded hormone therapy for arterial events. In a US Veterans Affairs cohort of 1,105,082 veterans (Streed 2025; read in primary), recorded feminising hormone therapy showed no statistically detectable association with incident atherosclerotic cardiovascular disease relative to trans veterans with no recorded hormone therapy (HR 0.99, 0.89–1.09, adjusted for age, race, ethnicity and sexual orientation; 1.02, 0.91–1.13 on full adjustment). The contrast is weaker than a within-population comparison: the transfeminine stratum was defined by receipt of feminising therapy, the no-recorded-therapy stratum is almost entirely an algorithmically “uncategorised” trans group, gender identity was inferred by an algorithm with low positive predictive value, hormones obtained outside the VA are uncaptured, and the outcome is a composite of myocardial infarction, ischaemic stroke, revascularisation and cardiac death. Against cisgender men, transfeminine veterans had a lower hazard (0.86, 0.79–0.95), attenuating to 0.91 (0.83–1.00) on full adjustment; trans veterans overall had a higher hazard than cisgender women (1.52; 1.25 fully adjusted) and a slightly lower hazard than cisgender men (0.92; 0.96). Cross-sectional survey studies (Huo 2024, All of Us; Federico 2025 and Saleh 2025, BRFSS; abstract-level) report higher odds of self-reported stroke or myocardial infarction among transgender people than cisgender comparators without hormone stratification, and attribute much of the difference to social determinants and conventional risk factors; they are noted, not graded.

C.2 — Myocardial infarction

Among the arterial outcomes reviewed, myocardial infarction shows the strongest comparator difference in the latest analysis. Observed incidence versus male reference populations was lower in the SES-adjusted 2026 Amsterdam data (against general-population men) (0.50, 0.32–0.71) and showed no detectable difference in Kaiser (0.9, 0.6–1.5). Against female reference populations the point estimates were higher (van Zijverden 1.30 against general-population women, not significant, in the SES-adjusted model — 1.57, significant, without SES adjustment; Kaiser 1.8). In the Amsterdam analysis, myocardial-infarction incidence was lower than the male reference population and its point estimate higher than the female reference; these comparisons do not identify which hormonal or other factors generated that pattern. The expanded Kaiser initiation report likewise found no statistically detectable MI excess against cisgender men (18 events; HR 0.7, 0.4–1.2) and higher incidence against cisgender women (2.1, 1.1–3.8) (Goodman & Zhang 2021); these remain external-comparator associations from the same Kaiser lineage. There is no venous-style mechanism to invoke and no consistent excess across comparators to explain — but the reassuring reading demands the same scrutiny as any convenient finding, and the candidate explanations for a lower observed SIR must be kept distinct rather than lumped as “bias”: residual confounding (including differential smoking); selection and survivor effects; healthy-user or healthcare-engagement effects; greater preventive treatment of cardiovascular risk factors (which would lower true incidence, not merely its detection); and outcome misclassification (which would explain a lower SIR only if silent events or their capture differed systematically between the cohort and the reference population). The defensible statement is narrow: the latest analysis found lower observed MI incidence than standardised general-population male reference rates, Kaiser found no detectable difference, and a cardioprotective causal effect of feminising therapy has not been established. The clinical task is management of conventional atherosclerotic risk factors — smoking, hypertension, diabetes and dyslipidaemia — with stroke-specific factors, including migraine with aura, assessed separately, alongside review of the hormone regimen.

C.3 — The transmasculine mirror (signpost to ER-023)

The same contemporary Amsterdam analysis reported stronger arterial associations in testosterone-treated trans men: a myocardial-infarction SIR of 4.20 (2.72–6.01) versus general-population women, tending higher even against general-population men (1.51, 0.98–2.16), with a raised cerebrovascular SIR (1.55). This warrants separate assessment in ER-023, and van Zijverden’s own conclusion is that cardiovascular risk management should be prioritised in trans men. It does not resolve the long-term arterial uncertainties that remain in transfeminine care — duration, ageing, regimen, and the out-of-scope outcomes below.

Feeding the corpus argument

Part C’s contribution is a boundary. The venous story (Parts A–B) is a reproducible, approximately twofold association, with several potentially modifiable levers whose preventable fraction is unquantified. The arterial story is not its extension: the principal transfeminine cohorts do not show higher overall MI incidence, and do not consistently show higher stroke incidence, relative to male reference populations, and one VA analysis found no statistically detectable association between recorded feminising therapy and composite atherosclerotic events relative to trans veterans with no recorded therapy — exposure and gender-classification limits prevent it from functioning as a clean treated-versus-untreated counterfactual; these comparisons do not identify the causal effect of therapy, and must not be read as demonstrated cardioprotection. Collapsing venous and arterial into one elevated “cardiovascular risk” — a common conceptual error — is what the separate grading exists to prevent; the reciprocal error, reading a lower comparator SIR as proof of benefit, is the one Part C guards against explicitly.

Scope note

ER-018 grades venous thromboembolism, myocardial infarction and ischaemic stroke. Other cardiovascular outcomes — heart failure, arrhythmia, hypertension as an endpoint, cardiovascular mortality — are outside its scope and are not assessed here. The title names these three outcomes for that reason.

Further evidence recorded at version 1.1

Added at v1.1; not graded. Access level stated for each source.

Two further analyses are recorded here and not graded. Balshi 2026 (Am J Cardiol, journal article published online ahead of print on 24 September 2026; abstract read, full text not obtained) is a propensity-matched multicentre analysis of 36,052 transgender and gender-diverse people against 36,052 cisgender people, reporting higher acute myocardial infarction (RR 1.64, 95% CI 1.38–1.94) and VTE (RR 1.36, 1.18–1.57). It pools all gender groups without hormone stratification and was matched on demographics only, so it cannot be set beside the trans-women estimates of Parts B and C; the symmetric standard requires it to be shown because it cuts against the arterial reassurance. Saxby 2026 (Lancet Reg Health West Pac, published 9 February 2026 — within v1.0’s evidence window, and missed by v1.0’s purposive discovery; full text read) is a national Australian cohort reporting higher cardiovascular-disease mortality (ischaemic heart, cerebrovascular and other circulatory deaths) among 19,347 people assigned male at birth who had started gender-affirming hormone therapy than among general-population males attending a GP (HR 2.60, 2.22–3.05), weighted for age and calendar time only, with age-band estimates that are imprecise and, except at 40–59 (1.54, 1.02–2.31), include no excess, and with no VTE-, MI- or stroke-specific figures. Mortality is outside ER-018’s scope, and the composite is recorded so that its omission is not mistaken for ignorance of it.

Provenance and verification (Part C)

• Read in primary: van Zijverden 2026 (10.1093/eurheartj/ehaf837) — the load-bearing arterial source, read for what it does and does not establish (comparator associations, not treatment effects; no lifestyle adjustment in the main model); Getahun 2018 (10.7326/M17-2785); Nota 2019 (10.1161/CIRCULATIONAHA.118.038584).
• Read in source (conference abstract; no fuller publication identified as of the 13 October 2026 search): Manchkanti 2023 (Blood 2023;142(suppl 1):1282) — directional counterpoint only. Read in primary (v1.1): Streed 2025. Read in full (funder final research report, r8): Goodman & Zhang 2021 — higher ischaemic-stroke estimates in the expanded Kaiser initiation cohort. Read in full (v1.1; narrative review): Skeith & Bates 2026. Abstract-level: Huo 2024; Federico 2025; Saleh 2025; Balshi 2026; Vecchiato 2026 (expert opinion).
• Independence (G7): van Zijverden takes precedence over Nota but is the same Amsterdam lineage; original Getahun is consistent with no detectable overall MI excess against men, while the expanded Kaiser initiation analysis reports higher stroke incidence.
• Not claimed: no extension of Part A’s mechanism to arterial events; no protective causal claim for oestradiol; no adoption of the authors’ mediational interpretation as fact; no transmasculine estimate beyond the ER-023 signpost.

Part D — Management

Part D translates the graded evidence of Parts A–C into two questions: who carries the venous risk, and what can be changed. It is not a prescribing protocol and not a policy position; it should not be used to start, stop or withhold treatment, and no decision should rest on it alone. It carries a standing frame: contemporary cohorts show an approximately twofold relative VTE association, while the absolute increment is baseline-risk dependent and the proportion causally attributable to contemporary prescribed oestradiol remains uncertain; several potentially modifiable treatment- and patient-level factors can be addressed — though the degree to which addressing them reduces clinical events in transfeminine populations is not quantified. That sits opposite a benefit that matters to patients: gender-affirming hormone therapy is desired and clinically important to many, and a systematic review of predominantly observational studies associates it with improved quality of life and reduced depression and anxiety, on low-strength evidence (Baker 2021) — though selection, concurrent care and the absence of randomised comparison limit causal attribution, and evidence on suicide attempts and mortality is weaker still and should not be collapsed with symptom measures into one figure. This benefit is graded on the same four axes as the harms in the front-matter mental-health declaration, and held to the same standard — not upgraded because it is the finding the author would prefer. Withholding or interrupting desired therapy may have psychological consequences and, particularly with prolonged interruption or after gonadectomy, physical consequences; those effects are not quantified in this review, and they belong in shared decision-making alongside thrombotic risk.

D.1 — Who: risk stratification

The events appear to cluster (B1), but the evidence is aggregate-level and is not a validated prediction tool. No transfeminine-specific VTE risk score exists.

Associated with fewer observed events (cohort level): younger average age and shorter average duration — study series with mean age under ~37.5 years or mean therapy under ~53 months reported few events. These are aggregate associations, not individual thresholds; 37.5 years and 53 months are data-derived splits, not clinical cut-offs, and none identifies a particular patient as being at population-baseline risk.

Established VTE risk factors (general venous medicine), which should be prioritised: personal or family history of VTE, high-risk thrombophilia, active malignancy, recent major surgery, immobilisation, and obesity, along with older age.

Treatment-related considerations, graded by evidential status (not equal in weight): strong historical concern — ethinylestradiol; indirect (cisgender/menopausal) concern — conjugated equine oestrogen and oral route; biologically plausible but unvalidated for trans VTE outcomes — higher oestradiol dose and cyproterone co-treatment.

A note on the cardiometabolic factors. Hypertension, dyslipidaemia and diabetes appeared in a small cohort’s cases, but they are stronger arterial than direct venous predictors, and that cohort had sparse events; they warrant management as part of overall vascular care, not treatment as established venous predictors. And some may change during long-term therapy, so the cohorts cannot determine whether they preceded treatment, arose independently, or partly mediated risk.

D.2 — What: the modifiable levers, graded by evidence strength

Molecule is the clearest oestrogen-formulation intervention: avoiding ethinylestradiol is well-supported; preferring oestradiol to CEE is reasonable but rests on indirect evidence. WPATH SOC-8 aligns, and its grading matches the evidence weight — it recommends (strong) against ethinylestradiol (Statement 12.13) and suggests (weak) against conjugated oestrogens where oestradiol is available (12.15). In a patient already receiving contemporary 17β-oestradiol, individual and transient VTE risk factors remain important and should be addressed; their contribution relative to any residual formulation- or route-associated risk has not been quantified.

Route is a defensible but inferred preference for higher-risk patients — B2a graded it an extrapolation, and Part D does not upgrade it. WPATH SOC-8 addresses this directly but as a weak recommendation: Statement 12.14 suggests (not the stronger “recommends”) transdermal oestrogen for those at higher VTE risk “based on age > 45 years or a previous history of venous thromboembolism”. Its supporting text (under Statement 12.11) notes that transdermal oestrogen with concomitant anticoagulation may lower risk in those with non-modifiable risk factors, but that data to guide such decisions are limited — expert risk-management guidance consistent with B2a’s grade, not trans-specific outcome validation. The age-45 criterion is a recommendation trigger for considering transdermal oestradiol, not evidence that risk changes discontinuously at 45; older age is a continuous baseline-risk consideration.

Anti-androgen. Cyproterone has measurable effects on selected haemostatic markers in trans studies (Schutte’s platelet/fibrinogen changes, Toorians’ APC rise), though in the same clinic’s study cyproterone alone did not change tPA or PAI-1 (Giltay 2000); its independent contribution to clinical VTE risk has not been quantified. ESTHER does not supply a risk-positive signal for it (B2c): cyproterone is a pregnane derivative, and that class was not associated with VTE in menopausal therapy. No study isolates a cyproterone-dose–VTE relationship, and the study built to compare doses (Kuijpers, 882 trans women) had too few events to test thrombosis. Kuijpers observed similar testosterone suppression across cyproterone doses in a longitudinal dose-analysis cohort of 882 trans women, with less prolactin and HDL-cholesterol effect at lower doses; only four participants started on 10 mg, doses could change during follow-up, and the analyses used repeated measurements, so this is observational efficacy evidence, not a randomised equivalence trial — so use the lowest effective dose, on grounds of efficacy, side effects and the cumulative-dose meningioma concern below; no VTE-prevention benefit of cyproterone dose reduction is established. Cyproterone’s principal established cumulative-dose concern is meningioma, not VTE: the EMA’s safety committee (PRAC) recommended, and the CMDh adopted by consensus on 26 March 2020, restrictions on cyproterone at daily doses of 10 mg or more — for hirsutism, androgenic alopecia, acne and seborrhoea, to use only once other options, including lower doses, have failed, with gradual reduction to the lowest effective dose after clinical improvement; for “reduction of sex drive in sexual deviations in men”, to use only when other treatments are not suitable; and with its use in prostate cancer unchanged — because meningioma risk rises with cumulative dose. Meningiomas have been reported primarily at doses of 25 mg/day and above, after prolonged (several-year) exposure, with the tumour rare overall (an estimated 1 to 10 per 10,000 people, depending on dose and duration). Cyproterone-containing products are contraindicated in patients with a current or previous meningioma, and if a meningioma is diagnosed during treatment, all cyproterone-containing products must be permanently discontinued (EMA/70255/2020, 14 February 2020; CMDh position, EMA/147755/2020, 27 March 2020). This is not a transgender-specific ruling, but a cumulative-dose concern directly relevant to off-label transfeminine use — and it reinforces the dose-minimisation point above. Cyproterone’s regulatory status is jurisdiction-specific: cyproterone-containing medicines are authorised in multiple European jurisdictions through national procedures, and in Canada (indicated there for the palliative treatment of advanced prostatic carcinoma), with licensed indications and availability varying by jurisdiction and feminising use off-label; it is not FDA-approved in the United States. Where it is unavailable or unsuitable, alternatives include spironolactone, GnRH analogues, oestradiol regimens that achieve adequate androgen suppression without a separate anti-androgen, or surgical gonadal suppression where independently indicated. Where appropriate and accessible, a GnRH agonist or spironolactone may avoid cyproterone; selection should weigh efficacy, cost, renal function, potassium, blood pressure, volume-depletion symptoms and urinary frequency (spironolactone), administration burden, bone health and flare (GnRH agonist), and patient preference — not a universal hierarchy.

Dose and conventional factors follow B3 and general medicine: avoid supraphysiological exposure, interpreting levels against the guideline target with sampling timing and assay specified (peak versus trough diverge on injectable and sublingual regimens), and address smoking, obesity, mobility, blood pressure, lipids and glycaemia as overall vascular care — while prioritising the established VTE factors of D.1.

D.3 — Thrombophilia and screening

Routine population screening before therapy is not recommended, because thrombophilia testing has low yield and uncertain utility in unselected patients; testing should be targeted where a personal VTE history or a strong family history suggestive of high-risk inherited thrombophilia means the result would change management (Hembree 2017; ASH 2024). This concerns screening before therapy in an asymptomatic person; it does not address clinically indicated thrombophilia or antiphospholipid testing after a documented VTE, where testing decisions depend on the event’s context and on whether a result would alter management. A history of VTE, high-risk thrombophilia, antiphospholipid syndrome, active malignancy or myeloproliferative disease requires individualised, haematology-informed assessment — these are not equivalent (antiphospholipid syndrome is not heterozygous factor V Leiden), are not automatically permanent contraindications, but may materially alter formulation, timing and anticoagulation decisions.

Two further sources point the same way. Ott 2010 (read in primary; 251 people, 162 trans women, transdermal oestradiol regimens, no VTE over a mean of about four to five years, activated-protein-C resistance in 7.2%) concluded that “general screening for thrombophilic defects in transsexual patients is not recommended”, restricting testing to people with a personal or family VTE history; a zero-event single-centre series is not load-bearing. A prospective Italian cohort that screened all 114 trans people starting hormone therapy found hereditary thrombophilia in 9.6% (95% CI 4.2–15.1) — a prevalence its authors describe as consistent with general-population estimates — and no antiphospholipid antibodies; carriers more often had a personal (18.2% vs 0%) or family history of VTE (45.4% vs 14.7%), and no VTE occurred in carriers or non-carriers over a median fifteen months under individualised, haematology-informed regimens (Campello 2026; read in primary). With no comparator and 114 participants, its authors state that the absence of events “may reflect limited power rather than definitive safety”; they recommend screening only those with a personal or family history or multiple acquired risk factors, which is the targeted position above. Skeith & Bates 2026 reach the same position — “in most cases, thrombophilia screening before initiation of therapy is not recommended” — citing the Ott series.

D.4 — After a venous thromboembolism

Treat acute VTE according to standard thrombosis guidelines; suspected acute VTE is an urgent diagnostic matter and hormone decisions should not delay assessment. A direct oral anticoagulant is appropriate for many patients, but selection must account for renal function, malignancy, drug interactions and bleeding risk, and antiphospholipid syndrome requires specialist, haematology-led anticoagulant selection. The ASH review is an expert synthesis, not a transfeminine-specific guideline, and the underlying anticoagulation guidance is general. Gender-affirming hormone therapy use alone is not an indication for routine long-term primary anticoagulant prophylaxis (ASH 2024); standard prophylaxis remains indicated when established surgical, medical or immobilisation criteria are met.

Acute VTE should be treated according to standard thrombosis guidance. The decision then turns on whether the oestrogen exposure stops or continues. If gender-affirming oestrogen is discontinued, anticoagulation duration can be assessed using the usual provoking-factor, recurrence- and bleeding-risk framework. If oestrogen is continued, the exposure remains potentially relevant to recurrence: the 2024 ASH Education Program review suggests that people who develop VTE on gender-affirming oestrogen and wish to continue may do so “if a full-dose anticoagulant is continued concurrently”, and states that it does not recommend stopping anticoagulation while oestrogen continues. That position rests largely on extrapolation from cisgender hormone-associated VTE rather than transfeminine recurrence trials. The largest supporting analysis (Martinelli 2016, from the EINSTEIN DVT/PE trials, read in primary) found recurrent VTE incidence of 3.7%/year on hormonal therapy versus 4.7%/year off during therapeutic anticoagulation, adjusted hazard ratio 0.56 (95% CI 0.23–1.39) — no detected increase, not proven safety; it excluded its two transgender participants (“2 patients with gender reassignment were excluded”), studied predominantly ethinylestradiol contraception, and says nothing about continued oestrogen after anticoagulation stops. A 2026 haematology review takes the same position — “ongoing, well-managed anticoagulant therapy can allow for continued use of hormone therapy”, while most people with hormone-associated VTE can stop anticoagulation after three to six months “as long as hormone therapy has been stopped” — and judges that the cisgender evidence “can probably be extrapolated to transfeminine persons” (Skeith & Bates 2026); that is expert extrapolation drawing partly on Martinelli, not independent transfeminine evidence. Where the anti-androgen is cyproterone, its Canadian product monograph lists “existing thromboembolic processes” as a contraindication and advises discontinuation “at the first sign of thrombophlebitis or thromboembolism” (in its licensed prostate-cancer population), so continuing cyproterone after a VTE departs from product labelling and an alternative anti-androgen merits consideration. Where treatment continues, formulation, dose and route should be reviewed — commonly favouring transdermal 17β-oestradiol — though a transdermal preference is not shown to eliminate recurrence risk. Where anticoagulation is continued indefinitely while oestrogen continues, the ongoing indication, recurrence risk, bleeding risk, concomitant medicines and patient preference should be reassessed periodically. Whether gender-affirming therapy continues and how long anticoagulation continues are separate decisions, and duration should be individualised with thrombosis expertise. Cancer-associated VTE, antiphospholipid syndrome and recurrent VTE each require specialist assessment of hormone exposure, anticoagulant choice, recurrence risk and bleeding risk; the general approach above should not be applied automatically to them. Indefinite anticoagulation exchanges thrombotic risk for a bleeding burden that belongs in the shared decision.

D.5 — Perioperative management — signpost only

ER-018 does not adjudicate perioperative hormone management. Current low-event observational evidence has not demonstrated a higher perioperative VTE rate with continuation of contemporary hormone therapy, and no evidence demonstrates that routine cessation reduces VTE. The comparative events are in single digits. In primary vaginoplasty: one event among 190 cases with oestrogen suspended for a week and none among 212 continued, groups separated by a 2018 policy change and all inpatients given heparin and compression devices (Kozato 2021); one subsegmental pulmonary embolism on day 80 among 238 who stopped oestrogen two weeks before surgery and none within ninety days among 91 who continued, with enoxaparin for all inpatients, group tracking calendar era, most continuing oral users switched to sublingual or intramuscular dosing, and a further event in the continuing group on day 97, outside the primary window (Kelmser 2025); and a 2022 meta-analysis pooling two vaginoplasty cohorts at OR 0.77 (95% CI 0.04–14.01), an interval excluding neither large benefit nor large harm (Badreddine 2022). In a genital-surgery cohort managed by an individualised algorithm, 1/138 continued versus 0/45 held, with the held group older and at higher baseline risk by design (Herndon 2024). In facial feminisation surgery, one VTE among 953 patients, in the full-dose-continued group, with mechanical prophylaxis only and no detected difference between groups (Li 2024): among 919 preoperative hormone users, 714 continued full dose, 197 reduced the dose and 8 held therapy, while the paper’s outcome table compares groups of 714 (full dose), 205 (dose decreased) and 34 (no hormone therapy), groupings its text does not fully reconcile (1/714 vs 0/205 vs 0/34); a systematic review of eleven facial-surgery studies counted 3/602 events after stopping versus 1/925 with continuation — the single continuation event being the Li patient — and drew no comparative conclusion (Laspro 2025). WPATH SOC-8 (Statement 12.18, with its supporting discussion under Statement 12.19) and Nolan & Cheung 2024 report no perioperative VTE increase with continuation, and a 2026 haematology review goes further, advocating continuation with thromboprophylaxis “depending on the clinical scenario” for transfeminine people, based on an informed discussion of benefits and drawbacks (Skeith & Bates 2026); that is expert opinion and does not change the low-event evidence. These studies are insufficient to establish equivalence across procedures, formulations and baseline-risk strata. Management should be individualised according to procedure-specific risk, previous VTE or thrombophilia, age, mobility and the planned thromboprophylaxis regimen; interrupting therapy has its own reported costs (hot flushes, mood change), documented so far in survey and anecdotal reports rather than outcome studies.

Provenance and verification (Part D)

• Read in primary: Kuijpers 2021 (10.1210/clinem/dgab427) — cyproterone dose-minimisation (efficacy/side-effects by dose: yes; dose–VTE: no; meningioma cumulative-dose concern). Read in full (regulatory and guideline documents): EMA cyproterone restriction (EMA/70255/2020, 14 February 2020) — meningioma cumulative-dose restriction, contraindication and permanent-discontinuation rule, read from the primary EMA document. WPATH SOC-8 Chapter 12 — Statements 12.13/12.14/12.15 verified and quoted at grade. Androcur product monograph (Health Canada) — approved product for palliative prostatic carcinoma; off-label for GAHT. ESTHER, Schutte, Toorians, Burgoon, Totaro, Getahun, Nota and van Zijverden: see Parts A–C.
• Read in primary (v1.1): Ott 2010 (supports, not load-bearing); Campello 2026; Kozato 2021; Kelmser 2025; Li 2024; Herndon 2024. Read in full (v1.1; syntheses): Badreddine 2022 (meta-analysis); Laspro 2025 (systematic review and cohort); Skeith & Bates 2026 (narrative review). Read in full (v1.1; regulatory): EMA/147755/2020; Androcur product monograph (Health Canada). Read in full (guidelines and reviews): WPATH SOC-8 Statement 12.18 and its supporting discussion under Statement 12.19; Hembree 2017; ASH 2024 (used directly for management guidance; not primary outcome evidence); Nolan & Cheung 2024.
• Not claimed: no cyproterone dose–VTE response; no primary-prophylaxis recommendation; no perioperative protocol; no universal anti-androgen hierarchy; no claim that the preventable fraction of the venous association is known.

Appendix — v1.1 update search

Database: PubMed (MEDLINE and in-process), via NCBI E-utilities. Run: 13 October 2026, 19:35 UTC. Date field: publication date [dp], 2024/01/01 to 2026/10/13 (171 records; 166 by entry date [edat], the difference being five 2023 e-publications).

Main string (171 records): (transgender[tiab] OR transfeminine[tiab] OR "trans women"[tiab] OR "transgender women"[tiab] OR "gender-affirming"[tiab] OR "gender affirming"[tiab] OR "cross-sex"[tiab] OR "gender diverse"[tiab]) AND (thromboembol*[tiab] OR thrombosis[tiab] OR "venous thrombo*"[tiab] OR "pulmonary embol*"[tiab] OR stroke[tiab] OR "cerebrovascular"[tiab] OR "myocardial infarction"[tiab] OR "cardiovascular"[tiab]) AND (estradiol[tiab] OR oestradiol[tiab] OR estrogen*[tiab] OR oestrogen*[tiab] OR hormone*[tiab])

Sensitivity strand 1 (221 records; no hormone block, MeSH added): ("Transgender Persons"[mh] OR "Gender Dysphoria"[mh] OR "Health Services for Transgender Persons"[mh] OR "Sex Reassignment Procedures"[mh] OR transgender*[tiab] OR "trans women"[tiab] OR "trans people"[tiab] OR "trans persons"[tiab] OR transfeminine[tiab] OR "gender-affirming"[tiab] OR "gender affirming"[tiab] OR "gender diverse"[tiab] OR "gender incongruence"[tiab] OR "gender dysphoria"[tiab]) AND ("Venous Thromboembolism"[mh] OR "Venous Thrombosis"[mh] OR "Pulmonary Embolism"[mh] OR "Stroke"[mh] OR "Myocardial Infarction"[mh] OR "Cardiovascular Diseases"[mh:noexp] OR thromboembol*[tiab] OR thrombos*[tiab] OR "venous thrombo*"[tiab] OR "pulmonary embol*"[tiab] OR stroke[tiab] OR "myocardial infarction"[tiab] OR "cardiovascular disease*"[tiab] OR "cardiovascular event*"[tiab] OR "cardiovascular outcome*"[tiab] OR "cardiovascular mortality"[tiab] OR VTE[tiab] OR MACE[tiab])

Sensitivity strand 2 (15 records; perioperative): (vaginoplasty[tiab] OR "gender-affirming surgery"[tiab] OR "gender affirming surgery"[tiab] OR "facial feminization"[tiab] OR "breast augmentation"[tiab] OR orchiectomy[tiab]) AND (transgender*[tiab] OR transfeminine[tiab] OR "gender-affirming"[tiab] OR "gender affirming"[tiab]) AND (thromboembol*[tiab] OR VTE[tiab] OR "venous thrombo*"[tiab] OR "pulmonary embol*"[tiab] OR "deep vein thrombosis"[tiab] OR DVT[tiab])

Selection: systematic reviews and meta-analyses; original cohort, case-control, registry or claims studies reporting VTE, MI or stroke in transgender women or people on feminising hormones; perioperative VTE and hormone continuation; post-VTE management. Excluded: case reports, masculinising-only and adolescent-only studies, surrogate-only studies, animal studies, editorials. Screening by one reviewer, not duplicated.

Known limits of the strings: the hormone block misses all-gender comparisons whose abstracts do not mention hormones (Balshi 2026 is retrieved only by strand 1); the outcome block misses outcome-agnostic hormone reviews (Cooney 2025 was added by hand). Older randomised route trials (Oger 2003; Post 2003), the 2022 perioperative meta-analysis (Badreddine 2022) and Smith 2004 fall outside the date window and were added from citation-chasing.

Mechanism search (added at r8). The update search above was restricted to 2024–2026 and excluded surrogate-only studies, so it could not establish currency for Part A. A separate search was run on 14 October 2026 at 02:25 UTC over the full window 1990–2026, combining the transgender terms with coagulation, haemostasis, thrombin, fibrin, fibrinolysis, protein C and S, activated protein C and platelet terms (74 records). It recovered the paired twelve-month cohorts and global-assay studies now carried in Part A (Scheres 2021; Bøgehave 2025 and 2026; Lim 2020; Bar-On 2026), three of which were already in the author’s archive and had been missed. The executable query was: (transgender*[tiab] OR transfeminine[tiab] OR "trans women"[tiab] OR "transgender women"[tiab] OR transwomen[tiab] OR transsexual*[tiab] OR "gender-affirming"[tiab] OR "gender affirming"[tiab] OR "cross-sex"[tiab] OR "Transgender Persons"[mh]) AND (coagulation[tiab] OR haemostasis[tiab] OR hemostasis[tiab] OR haemostatic[tiab] OR hemostatic[tiab] OR thrombin[tiab] OR fibrin*[tiab] OR fibrinoly*[tiab] OR "protein S"[tiab] OR "protein C"[tiab] OR "activated protein C"[tiab] OR platelet*[tiab] OR "factor VIII"[tiab] OR thromboelastograph*[tiab] OR "Blood Coagulation"[mh] OR "Hemostasis"[mh] OR "Fibrinolysis"[mh]) AND ("1990/01/01"[dp] : "2026/10/14"[dp]), publication-date field, inclusive upper bound 14 October 2026; the 74 PMIDs and their screening disposition are filed with the build record. Perioperative, surgical-technique and transmasculine-only records were excluded as before. Both this mechanism search and the clinical update search are to be re-run on the day of deposit.

Narrative and expert syntheses: the union of the three strings (247 records) contains 72 records indexed in PubMed as reviews. Narrative and expert syntheses were retained selectively, for specialist clinical framing and management positions (ASH 2024, Nolan & Cheung 2024, Skeith & Bates 2026, Vecchiato 2026), not comprehensively; others retrieved by the same strings, such as Schachter 2025 (Vasc Med; PMID 40366074), were not carried. No narrative synthesis contributes a figure to any grade.

Screening decisions revised at v1.1 (r5): Slack 2024 (Endocr Pract; PMID 39233010) was retrieved and at first not incorporated because only its abstract was available; it is now recorded in B1 at abstract level as a non-coequal counterpoint, because other abstract-level evidence is admitted and the symmetric standard does not permit excluding a reassuring study on that ground alone. Vecchiato 2026 (Eur J Prev Cardiol; PMID 42858955; published online 11 October 2026, PubMed entry 10 October 2026) was retrieved by the main string and strand 1 and screened out as expert opinion; it is now recorded as an abstract-level secondary synthesis, for consistency with the inclusion of Skeith & Bates 2026. It was not missed through indexing lag. Kelmser 2025 and Campello 2026 were retrieved by the search and are incorporated in D.5 and D.3.

Re-run: the three strings were re-run unchanged on 13 October 2026 at 22:08 UTC with the same date field; the counts were identical (171, 221, 15); identical counts do not by themselves prove an identical record set, which would require comparing the PMID lists. The clinical and mechanism searches are to be re-run on the day of deposit and any new record reported here.

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Goodman M, Zhang Q. Stroke and blood clot risk in transgender women taking hormones. Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2021. PCORI Final Research Report. doi:10.25302/05.2021.AD.SS4532 [funder final research report; not a journal article]

Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(11):3869–3903. doi:10.1210/jc.2017-01658

Herndon J, Gupta N, Davidge-Pitts C, et al. Genital surgery outcomes using an individualized algorithm for hormone management in transfeminine individuals. J Clin Endocrinol Metab. 2024;109(11):2774–2783. doi:10.1210/clinem/dgae269

Huo S, Rivier CA, Clocchiatti-Tuozzo S, et al. Brain health outcomes in sexual and gender minority groups: results from the All of Us Research Program. Neurology. 2024;103(8):e209863. doi:10.1212/WNL.0000000000209863 [abstract]

Kelmser EC, Parekh A, LaVasseur C, et al. Postoperative venous thromboembolism in transgender patients receiving estrogen-based hormone therapy. Res Pract Thromb Haemost. 2025;9(4):102884. doi:10.1016/j.rpth.2025.102884

King H, Padilla Kelley T, Shatzel JJ. Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk. Hematology Am Soc Hematol Educ Program. 2024;2024:652–663. doi:10.1182/hematology.2024000592

Kozato A, Fox GWC, Yong PC, et al. No venous thromboembolism increase among transgender female patients remaining on estrogen for gender-affirming surgery. J Clin Endocrinol Metab. 2021;106(4):e1586–e1590. doi:10.1210/clinem/dgaa966

Kuijpers SME, Wiepjes CM, Conemans EB, Fisher AD, T’Sjoen G, den Heijer M. Toward a lowest effective dose of cyproterone acetate in trans women: results from the ENIGI study. J Clin Endocrinol Metab. 2021;106(10):e3936–e3945. doi:10.1210/clinem/dgab427

Laspro M, Hoffman A, Chinta S, et al. The effects of perioperative gender-affirming hormone therapy on facial feminization surgery adverse events, facial features addressed, and esthetic satisfaction: a multimodal analysis. J Craniofac Surg. 2025;36(2):600–604. doi:10.1097/SCS.0000000000010840

Li AY, Park MJ, Fick J, Ousterhout DK, Deschamps-Braly JC. Perioperative estrogen hormonal therapy does not increase venous thromboembolism risk in facial feminization surgery. Plast Reconstr Surg. 2024;154(6):1309–1315. doi:10.1097/PRS.0000000000011437

Lim HY, Leemaqz SY, Torkamani N, et al. Global coagulation assays in transgender women on oral and transdermal estradiol therapy. J Clin Endocrinol Metab. 2020;105(7):e2369–e2377. doi:10.1210/clinem/dgaa262 [abstract]

Manchkanti S, Dayal S, Ramakrishna A, Streeter J. Transgender women on estrogen have a lower burden of thrombotic events compared to cisgender men: a nationwide hospital-based survey. Blood. 2023;142(suppl 1):1282. doi:10.1182/blood-2023-185224

Martinelli I, Lensing AWA, Middeldorp S, et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood. 2016;127(11):1417–1425. doi:10.1182/blood-2015-08-665927

Nolan BJ, Cheung AS. Gender-affirming hormone therapy for transgender and gender-diverse adults in Australia. Intern Med J. 2024;54(9):1450–1457. doi:10.1111/imj.16413

Nolan BJ, Cheung AS. Relationship between serum estradiol concentrations and clinical outcomes in transgender individuals undergoing feminizing hormone therapy: a narrative review. Transgend Health. 2021;6(3):125–131. doi:10.1089/trgh.2020.0077

Nota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Kreukels BPC, den Heijer M. Occurrence of acute cardiovascular events in transgender individuals receiving hormone therapy. Circulation. 2019;139(11):1461–1462. doi:10.1161/CIRCULATIONAHA.118.038584

Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol. 2003;23(9):1671–1676. doi:10.1161/01.ATV.0000087141.05044.1F

Ott J, Kaufmann U, Bentz E-K, Huber JC, Tempfer CB. Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy. Fertil Steril. 2010;93(4):1267–1272. doi:10.1016/j.fertnstert.2008.12.017

Post MS, Thomassen MCLGD, van der Mooren MJ, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol. 2003;23(6):1116–1121. doi:10.1161/01.ATV.0000074146.36646.C8

Pyra M, Casimiro I, Rusie L, et al. An observational study of hypertension and thromboembolism among transgender patients using gender-affirming hormone therapy. Transgend Health. 2020;5(1):1–9. doi:10.1089/trgh.2019.0061

Rothman MS, Ariel D, Kelley C, et al. The use of injectable estradiol in transgender and gender diverse adults: a scoping review of dose and serum estradiol levels. Endocr Pract. 2024;30(9):870–878. doi:10.1016/j.eprac.2024.05.008 [read from accepted pre-proof]

Saleh AK, Bowman SE, Scheinuk JE, et al. Impact of social determinants of health on atherosclerotic cardiovascular disease in transgender individuals. Mayo Clin Proc. 2025;100(12):2172–2183. doi:10.1016/j.mayocp.2024.12.023 [abstract]

Saxby K, Bailey S, Petrie D, Nolan BJ. All-cause and cause-specific mortality among transgender and gender diverse people: a nationwide cohort study in Australia. Lancet Reg Health West Pac. 2026;67:101813. doi:10.1016/j.lanwpc.2026.101813 (published 9 February 2026; full text, PMC12914191)

Saxby K, Buchmueller T, Carpenter CS, Coman C, Nolan BJ. Mental health treatment among transgender and gender diverse people following gender affirming hormone therapy: evidence from whole-of-population Australian administrative data. EClinicalMedicine. 2026;92:103765. doi:10.1016/j.eclinm.2026.103765

Schachter H, Blaszczak J, Barnes GD. Review of venous thromboembolism (VTE) risk, evaluation, and treatment in individuals on estrogen-based gender-affirming hormone therapy. Vasc Med. 2025;30(4):488–498. doi:10.1177/1358863X251334141 [retrieved by the search; not carried]

Scheres LJJ, Selier NLD, Nota NM, van Diemen JJK, Cannegieter SC, den Heijer M. Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen. J Thromb Haemost. 2021;19(4):1029–1037. doi:10.1111/jth.15256

Schutte MH, Kleemann R, Nota NM, et al. The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis. PLoS One. 2022;17(3):e0261312. doi:10.1371/journal.pone.0261312

Seal LJ, Franklin S, Richards C, Shishkareva A, Sinclaire C, Barrett J. Predictive markers for mammoplasty and a comparison of side effect profiles in transwomen taking various hormonal regimens. J Clin Endocrinol Metab. 2012;97(12):4422–4428. doi:10.1210/jc.2012-2030

Skeith L, Bates SM. Sex hormone influences on venous thrombotic and cardiovascular risk. N Engl J Med. 2026;394(15):1514–1528. doi:10.1056/NEJMra2202438

Slack DJ, Krishnamurthy N, Chen D, Contreras-Castro FG, Safer JD. Evaluating the risk of venous thromboembolism in transfeminine and gender diverse people: a retrospective analysis. Endocr Pract. 2024;30(11):1066–1072. doi:10.1016/j.eprac.2024.08.014 [abstract]

Smith NL, Heckbert SR, Lemaitre RN, et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA. 2004;292(13):1581–1587. doi:10.1001/jama.292.13.1581

Streed CG Jr, Duncan MS, Heier KR, et al. Incident atherosclerotic cardiovascular disease among veterans by gender identity: a cohort study. J Gen Intern Med. 2025;40(13):3149–3158. doi:10.1007/s11606-025-09701-5

Toorians AWFT, Thomassen MCLGD, Zweegman S, et al. Venous thrombosis and changes of haemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab. 2003;88(12):5723–5729. doi:10.1210/jc.2003-030520

Totaro M, Palazzi S, Castellini C, et al. Risk of venous thromboembolism in transgender people undergoing hormone feminizing therapy: a systematic review and meta-analysis. Front Endocrinol. 2021;12:741866. doi:10.3389/fendo.2021.741866

van Kesteren PJM, Asscheman H, Megens JAJ, Gooren LJG. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf). 1997;47(3):337–342. doi:10.1046/j.1365-2265.1997.2601068.x

van Zijverden LM, Wiepjes CM, van Diemen JJK, Thijs A, den Heijer M. Cardiovascular disease in transgender people: a systematic review and meta-analysis. Eur J Endocrinol. 2024;190(2):S13–S24. doi:10.1093/ejendo/lvad170

van Zijverden LM, Thijs A, van Diemen JJK, Wiepjes CM, den Heijer M. Transgender persons receiving gender-affirming hormone therapy: risk of acute cardiovascular events in a Dutch cohort study. Eur Heart J. 2026;47(21):2660–2669. doi:10.1093/eurheartj/ehaf837 (published online 4 November 2025)

Vecchiato M, van Zijverden LM, van Heesewijk J, et al. Cardiovascular health in transgender and gender diverse individuals: an expert opinion on gender-affirming hormone therapy, risk assessment and clinical management. Eur J Prev Cardiol. 2026. Published online ahead of print 11 October 2026. doi:10.1093/eurjpc/zwag528 [abstract]

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810. doi:10.1136/bmj.k4810

Claim-to-reference map

For each load-bearing claim: the source(s) cited, what the source actually shows, and a support check — verifying that each citation resolves to a source that supports the claim, not merely that the citation resolves. Cross-referenced against the study-overlap matrix so that no figure re-cited across a single cohort lineage is counted as independent corroboration, with a population-directness flag on every claim that borrows from a cisgender source.

Support-check key: ✓ direct support · ⚠ supported with population/scope caveat (flagged in text) · ⟳ two-lineage corroboration verified · ◐ observed-comparator, not causal · ○ primary support unavailable — the claim rests on an unobtained source, or on a secondary characterisation substituting for an unavailable primary (flagged). A systematic review used deliberately as synthesis-level evidence is not marked ○

Part A — Mechanism

Part B1 — VTE Magnitude

Part B2 — Route and Molecule

Part B3 — Level and Injectable

Part C — Arterial

Part D — Management

Independence audit (cross-referenced to the study-overlap matrix)

• Two independent clinical cohort lineages contribute the principal VTE and arterial comparator estimates. Their VTE associations are similarly directed (Getahun ⟳ van Zijverden, ~2×); their arterial estimates differ in magnitude, comparator and subgroup. Within-lineage updates (including the expanded Kaiser report) and pooled syntheses are not independent replications. Independent cisgender route datasets support an indirect route association, not a demonstrated transfeminine reduction in events. Claims resting on one lineage or one source are marked accordingly.
• No claim in this map cites Totaro as independent confirmation of Getahun, Nota or van Kesteren — Totaro pools them.
• No Amsterdam-lineage figure is counted twice: van Zijverden supersedes Nota (not additive); van Kesteren and Asscheman appear only as B1’s ungraded historical anchor and in the transmission appendix.
• Every cisgender-sourced claim carries a population flag (⚠): route (ESTHER, Vinogradova), progestogen class (ESTHER), post-VTE continuation (Martinelli). None is applied to trans populations without that flag.
• Glintborg is not cited for a VTE magnitude claim — only for independence, GAHT-non-mediation, and surveillance-bias corroboration, consistent with its composite-outcome design.

Study-overlap matrix

Which cohorts are independent, which share a lineage, which pool the others

This map prevents counting one dataset’s finding as independent corroboration when it appears under several citations — distinguishing genuinely independent facts from the same fact re-cited. Every relationship below is drawn from sources read in full; items not read in full are marked.

The core principle for this review

For venous thromboembolism, there are effectively two independent cohort lineages supplying the load-bearing comparative incidence estimates, other independent trans-direct datasets that estimate something different (Glintborg 2022; Slack 2024), plus one meta-analysis that pools them and several single-source or cisgender inputs. Numerical agreement between the two lineages is corroboration; numerical agreement within a lineage (or a meta-analysis quoting its members) is not.

Cluster 1 — The Amsterdam lineage (ACOG / Centre of Expertise on Gender Dysphoria, VUmc / Amsterdam UMC)

One institutional cohort, sampled and re-analysed across decades. Treat all of these as NON-independent of one another.

Mechanism sub-lineage (same institution, VUmc/Amsterdam gender clinic, and the ENIGI network built on it). Three dependence labels are used below: confirmed participant overlap; possible participant overlap; and shared institution or network without demonstrated participant overlap. The same clinic in different decades does not by itself prove the same participants.

Consequence: the mechanism argument (Part A) rests substantially on one clinic’s lineage and on the ENIGI recruitment stream that shares its Amsterdam arm (Scheres 2021; Bøgehave 2025, 2026), with da Cruz (Porto Alegre), Lim 2020 (Melbourne) and Bar-On 2026 (Tel Aviv) the independent mechanistic checks — the first two cross-sectional, the third a small prospective pilot, and the last two at abstract level. Flagged in Part A provenance.

Cluster 2 — Kaiser STRONG (US, independent)

Cluster 3 — Other trans-direct cohorts

Cluster 4 — The pooling meta-analysis (NOT independent corroboration)

Added at v1.1: van Zijverden 2024 (meta-analysis; full text) pools Getahun, Nota, Quinn 2017 (US Kaiser data, likely overlapping Getahun), Wierckx 2013, Karalexi, Caceres and Poteat — not independent of Clusters 1–2. Franco-Moreno 2025 (systematic review; abstract) pools five studies for its VTE estimate; its included-study list could not be obtained, so overlap with Getahun, Nota and Pyra cannot be excluded and it is treated as non-independent. Streed 2025 (US Veterans Affairs; read in primary) is an independent arterial cohort and the only one contrasting trans veterans with and without recorded hormone therapy; the strata were algorithmically derived, so the contrast is confounded with how gender identity was ascertained.

Cluster 5 — Cisgender / menopausal inputs (route & molecule; indirect population)

Cluster 6 — Secondary syntheses and guidelines (never primary outcome evidence)

Independence summary (the one-line answer for any figure)

• VTE magnitude ≈ 2×: corroborated by two independent lineages — Kaiser (Getahun) and Amsterdam (van Zijverden). Independent participants, though not independent of shared observational biases.
• Arterial. Myocardial infarction: Amsterdam reports lower incidence than male reference rates, and the original and expanded Kaiser analyses show no statistically detectable excess against men. Stroke: estimates differ across Amsterdam, the original Kaiser analysis and the expanded Kaiser initiation report (the last elevated). Manchkanti is a weak crude-proportion counterpoint, not an independent adjusted estimate of therapy’s effect. The expanded Kaiser report is the same lineage as Getahun, not a third; the pooled stroke estimate (van Zijverden 2024, RR 1.3, 1.0–1.8) is likewise less reassuring.
• Anything from Totaro: contains Getahun + Nota + van Kesteren — not independent of them.
• “45-fold” / “20-fold”: single Amsterdam-lineage population (van Kesteren is an update of Asscheman’s cohort); both read in primary; both observed-versus-expected against general-population rates. Historical anchor only, not graded.
• Mechanism (Part A): the Amsterdam clinic lineage and the ENIGI recruitment stream that shares it, with da Cruz, Lim and Bar-On as independent checks (two cross-sectional, one a small prospective pilot).
• Route/molecule: two independent cisgender datasets (ESTHER, Vinogradova); transfeminine route data only as external-comparator strata within the Kaiser lineage.

Not obtained: no cited source wholly unavailable. Abstract-level: Balshi, Franco-Moreno, Huo, Federico, Saleh, Slack, Vecchiato, Lim, Bar-On.

Appendix — Evidence transmission

This appendix documents examples identified during this review in which a figure or finding changed shape during secondary transmission. These cases demonstrate that clinically meaningful information can be lost or altered in transmission; they do not estimate how frequently this occurs in the wider literature, or whether transmission errors are more common than errors in primary studies. Each case is recorded because catching it is what the method is for; these are source-transmission observations, not graded clinical findings or estimates of their prevalence in the field, and where a primary could not be obtained the item is quarantined, not used.

The standing pattern

Among the sources checked for this review and its predecessors, several lost context or presented insufficiently explained denominators: a significant finding dropped from a secondary’s one-line summary; a sample size differing between a review’s body text and its own table; a striking figure re-cited across multiple reviews, all tracing to one primary. These examples concern omitted context, omitted additional findings, differently reported denominators and retrieval-version uncertainty. They show how summaries can lose clinically relevant information; they do not establish what the citing authors read, or why particular details were omitted. The defence is the same in each case: read the primary, and read it before quoting the secondary.

Four cases from this review, in order of how much they matter.

Case 1 — The “45-fold” figure: accurately reported, missing its comparator

What circulates. A “45-fold increased risk of venous thromboembolism (occurring in 6.3%)” in trans people treated with ethinylestradiol 100 µg plus cyproterone acetate 100 mg daily.

The attribution chain. The figure is attributed to Asscheman 1989 (Metabolism) by the ASH 2024 education review and by the Nolan & Cheung 2024 narrative review, in near-identical wording. The same Amsterdam population was updated in van Kesteren 1997, which reports 45 VTE events among 816 trans women (Table 4) — and the coincidence of “45 events” (van Kesteren) with “45-fold” (Asscheman) is what first raised the possibility of a count-to-fold conflation.

What the reading revised (v1.1). Both primaries have now been read, and the conflation hypothesis is refuted. Asscheman 1989 reports 19 venous thromboses or pulmonary emboli among 303 trans women against 0.42 expected — “a 45-fold increase” — and states the 6.3% (19/303) in its results; ASH 2024 and Nolan & Cheung 2024 therefore report the primary accurately, though both omit that the comparison is observed against expected general-population rates and that 45 of the 303 were on self-administered intramuscular oestradiol rather than the standard ethinylestradiol regimen. van Kesteren 1997 reports “a 20-fold increase” (SIR 19.56, 12.27–26.18), and itself explains the fall from 45-fold to 20-fold by the clinic’s 1989 move to transdermal oestradiol for those over 40. The v1.0 handling (unobtainable primary; twentyfold attributed but unverified) and the first v1.1 draft’s withdrawal of the twentyfold figure were both wrong.

Handling. Asscheman 1989 and van Kesteren 1997 are read in primary. Both figures are verified and recorded in B1’s historical anchor; neither enters the graded body, because each describes a deprecated high-dose oral regimen, compares observed events with expected general-population rates rather than a control group, and comes from the lineage already represented by van Zijverden 2026. The case stands as an example of a secondary-source figure that was accurate but stripped of its denominator and comparator.

Case 2 — A significant finding a secondary dropped: the Pyra progestin signal

What the secondary said. The ASH 2024 review characterised Pyra 2020 as finding “no association between thrombosis and gender-affirming hormone therapy as assessed by blood concentrations” — accurate, as far as it goes.

What the primary also said. Reading Pyra 2020 in full recovered a finding the secondary omitted: recent progestin prescription was associated with roughly threefold odds of thromboembolism (adjusted OR 2.95, 95% CI 1.02–8.57), with a much larger and far more imprecise estimate for medroxyprogesterone acetate that rests on a single event. Pyra’s outcome is a composite thromboembolism measure that includes arterial and superficial venous codes, not VTE alone. This is a significant, trans-direct association — and it is exactly the kind of finding that matters for the progestogen-co-exposure question this review takes up (B2c).

Why it matters. The study reported both a non-significant concentration association and a positive progestogen-prescription association; the secondary carried the first and dropped the second. Had this review cited Pyra through the secondary, as it initially did, it would have carried a partial reading of a paper it treated as evidence. The finding now appears in B2c, fully caveated (composite outcome, small event count, MPA not cyproterone, wide interval, US spironolactone-based cohort). This is the transmission thesis in miniature: the primary carried more than the summary of it.

Case 3 — Different denominators insufficiently explained in a secondary: the Kozato sample size

The discrepancy. The ASH 2024 review reports the Kozato perioperative cohort as N=402 in its body text and N=407 in its own summary table, for the same study. The body text carries the 190 + 212 hormone-management comparison groups and the table the 407 total; the figures are not reconciled in the review itself, and the primary reconciles them. This is differently reported denominators, insufficiently explained, rather than an arithmetic error.

Handling (revised at v1.1). The Kozato full text (read in primary) accounts for all 407 primary vaginoplasty cases: 190 with oestrogen suspended, 212 continued and 5 not on hormone therapy perioperatively (Table 3). ASH’s body text carries the 190 + 212 subtotal and its table the total. The discrepancy is ASH’s, and D.5 cites the primary directly.

Case 4 — A superseded copy in the retrieval layer, resolved by the correct primary

The version hazard. The source-retrieval connector held a copy of the Endocrine Society 2017 guideline flagged superseded, carrying a warning not to quote figures from it. The guideline is the common source for the serum-oestradiol monitoring range (100–200 pg/mL) cited across the field.

How it resolved — the archive gate working as designed. Rather than quote the figure from a flagged copy, the review initially held it as attributed-not-asserted. The author’s own archived copy was then confirmed to be the correct published version (Hembree 2017, Table 15), which verifies the figure directly. B3 now states it as verified. This is the transmission discipline running in the retrieval layer: a superseded copy in an automated source is exactly the kind of version hazard the field propagates unknowingly, and the safeguard is not to quote from a flagged source until the correct primary is in hand. Here the correct primary was in hand, and the figure holds. Recorded as a clean resolution, not an open issue.

A note on citation precision (not an error, a caution)

Getahun 2018 is variously cited with N=102,421 (the full matched cohort, including cisgender comparators) and with the 2,842 transfeminine figure (the overall transfeminine subgroup, not restricted to confirmed oestrogen recipients). Both are correct for what they describe; a claim about trans women that quotes the 102,421 figure has quietly borrowed the whole cohort’s N for a subgroup finding. This review uses the transfeminine figures throughout, and flags the distinction because the larger number circulates in secondary citations where the subgroup number is meant.