Transgender Estradiol: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Transgender Estradiol (NCT04036500), a na early/phase 1 study. The primary outcome is Maximum Serum Concentration of Estradiol.

2. Clinical Question

The study addresses a pharmacokinetic question: how estradiol concentrations in blood change after two routes of administration. Its brief summary notes interest in whether sublingual administration could offer an alternative to oral or transdermal formulations, and says that well-conducted studies in transgender populations had been lacking. The registered primary endpoint is a concentration measure, not a clinical outcome. A concentration profile can describe drug exposure over the specified observation period, but by itself it does not establish comparative safety, effectiveness, or longer-term effects.

The registry describes this as a pilot study and lists 11 participants enrolled. The primary result needed to answer the registered question—the maximum concentration for each route and the estimated contrast—is not reported in the registry record. As a result, the direction and size of any difference cannot be assessed from the posted results described in this record.

3. Trial Design

This completed early-phase study, NCT04036500, is titled “Transgender Estradiol,” with the official title “Sublingual Estradiol Versus Oral Estradiol in Transgender Women.” The listed phase is EARLY PHASE1, and the sponsor is the Medical College of Wisconsin. The registry lists enrollment of 11 and the condition Transgender Persons. The study started on 2019-09-23, reached primary completion on 2020-07-13, and has COMPLETED status.

The design is recorded as a single-group model, with no allocation and no masking. The arm description presents an ordered sequence: participants take estradiol 1 mg orally after a time 0 blood draw, followed by blood sampling at hours 0,1,2,3,4,6,8. After a wash-out period of at least one week, the description says the pharmacokinetics of sublingual estradiol are tested on the same ten participants. Thus, the route comparison is within participants and sequential, rather than a randomized comparison of independent groups. The record does not describe randomized assignment or a masked procedure.

The stated wash-out period is intended, in the registry wording, to allow clearance of the oral estradiol before the sublingual testing. The record does not give further details about how clearance was assessed, whether the wash-out could be extended, or how adherence to the sequence was monitored. Those details are not reported in the registry record.

Because participants receive both routes in a set order, route and period are not separated by randomization. General design considerations include the possibility that measurements may be influenced by order, timing, or participant-level differences; the registry does not state whether these issues were addressed analytically. The primary endpoint is maximum serum estradiol concentration over 8 hours. The record lists a secondary outcome, the ratio of estrone to estradiol, but does not report outcome estimates or analysis results.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: After the screening visit in which the pharmacist determined if there was metabolism alternating drugs being taken 10 patients were enrolled.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Serum Concentration of Estradiol, measured over 8 hours.

The primary endpoint is maximum serum concentration of estradiol, expressed in pg/mL, over an 8-hour timeframe. The registry specifies a mean as the measure of central tendency and standard deviation as the measure of dispersion. This endpoint is intended to capture the highest measured estradiol concentration during the specified observation window after administration by a given route. In pharmacokinetic studies, concentration measurements over time describe the blood-level profile following a dose; a maximum concentration is one summary of that profile.

Maximum concentration is useful for comparing the peak levels observed after oral and sublingual administration. It does not describe all aspects of exposure: for example, it does not alone summarize how long concentrations remain elevated or the total concentration across the observation period. Those are distinct questions and should not be inferred from this endpoint.

The registry describes blood draws at hours 0,1,2,3,4,6,8 for the oral administration, and its arm description indicates subsequent sublingual testing. The precise rule used to derive a maximum from the measurements, including how values between scheduled draws were handled, is not reported in the registry record. The route-specific means, standard deviations, and comparison are also not reported in the registry record. Consequently, the endpoint definition is available, but the primary finding cannot be interpreted from this record alone.

A maximum concentration is a laboratory measure rather than a direct measure of symptoms, quality of life, or longer-term health outcomes. A difference in this measure, if reported, would need to be interpreted as a difference in measured peak concentrations within this study, not as proof of a broader clinical benefit or harm.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a continuous primary outcome: maximum serum estradiol concentration, measured in pg/mL and summarized using a mean and standard deviation. It does not report the primary result or a statistical analysis plan. The concepts below explain how such statistics are generally interpreted; they should not be read as a description of analyses confirmed for this trial.

What does the mean describe?

For a continuous measure, the mean is a summary of the observed values. In this study, it would describe the average maximum concentration among the participants included in the analysis for a route. A mean gives a compact account of the group, but it does not show every participant's value or reveal the shape of the distribution. A few unusually high or low observations can influence it.

The standard deviation describes how spread out individual measurements are around the mean. It is not the same as the uncertainty around the mean. A standard deviation reflects variability among participant measurements, while uncertainty in an estimated mean or difference is commonly conveyed with a confidence interval. The registry specifies the standard deviation as the endpoint's dispersion measure but does not report values or confidence intervals.

How would a within-participant comparison work?

Because the arm description says the same participants were tested under both routes, a natural general approach would compare each participant's outcome under one route with that participant's outcome under the other. This differs from treating the route groups as unrelated samples. Pairing can remove some variation attributable to stable differences between participants, but it requires valid measurements under both conditions and an analysis that respects the pairing.

The registry record does not report whether the primary analysis used paired values, how incomplete pairs were handled, or whether another method was used. Nor does it state a model, covariates, or assumptions for the comparison. It would therefore be inappropriate to attribute any specific statistical test or model to the trial.

What does a confidence interval mean?

In general, a confidence interval gives a range of values compatible with the data and the estimation procedure, under its assumptions. It conveys precision as well as the direction and size of an estimated effect. A narrow interval indicates greater precision than a wide interval, while an interval spanning effects in more than one direction may leave the direction uncertain. A confidence interval is not a guarantee that the true value lies within that particular interval.

No confidence interval for the route comparison is reported in the registry record. Without an estimate and its uncertainty, readers cannot assess the precision of the primary comparison. A p-value, even if it were reported, would not replace an effect estimate and interval: it addresses compatibility with a specified null hypothesis under a statistical model, not the size or clinical importance of an effect.

Why does the measurement schedule matter?

A maximum is derived from measurements taken over time. The schedule in the oral description includes blood draws at hours 0,1,2,3,4,6,8. In general, a measured maximum is constrained by the timing and frequency of sampling: a peak occurring between scheduled measurements may not be directly observed. The record does not describe a method for estimating an unobserved peak or state whether the endpoint is strictly the largest observed value. Interpretation should therefore remain tied to the recorded endpoint and not assume a more detailed estimation procedure.

Pharmacokinetic data may also show skewness or unequal variability. In general, over-dispersion means that variability is greater than a model expects; if present, it can make standard errors and tests unreliable when the model does not account for it. The registry does not report distributional diagnostics, transformations, or methods for handling unequal variability. This is a general consideration, not evidence that over-dispersion occurred in this study.

How should planning calculations be read?

In general, a sample-size illustration based on an observed effect is a planning calculation. It asks how many participants per arm might be needed under stated assumptions to detect a chosen fraction of that effect at a specified power. It is not the number actually studied, evidence that the study had a particular power, or an estimate of what the trial would have found in a repeat study. Illustrations based on observed effects can also be uncertain, especially when the underlying study is small.

The registry description of planning assumptions refers to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also distinguishes participants per arm from total events for time-to-event calculations. This study is described as a single-group, sequential within-participant comparison, however, and the registry does not report the trial's own sample-size justification or design assumptions. The planning assumptions should not be mistaken for a registered analysis plan. No planning estimates are reported in the registry record.

What can be concluded from the statistical record?

The endpoint definition and design can be described, but the inferential results cannot. Route-specific summaries, a comparison estimate, uncertainty measures, p-values, and analysis details are not reported in the registry record. General statistical principles explain how those results could be read if reported; they cannot fill in missing estimates or establish a result for this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and identifies maximum serum concentration of estradiol as the primary outcome. It also lists the ratio of estrone to estradiol as a secondary outcome. The remaining outcome details, including their definitions and analysis status, are not reported in the registry record. The record lists zero analyses.

When a study evaluates multiple outcomes or conducts multiple statistical tests, the chance of finding at least one apparently notable result can increase. General statistical approaches may account for this through a prespecified hierarchy or adjustment, but the appropriate approach depends on the trial's planned questions. The registry record does not report whether any multiplicity strategy was planned or used, nor does it describe how primary and secondary outcomes would be interpreted together.

Missing-data handling is also not reported. The record does not state how many participants contributed primary endpoint measurements, whether any measurements were absent, or how incomplete concentration profiles or missing paired outcomes were treated. It does not describe imputation, exclusions, or sensitivity analyses. The enrollment figure is 11, while the safety record lists 10 at risk for each route; the reason for this difference and its relationship to the analysis population are not reported.

The record does not identify an intention-to-treat, per-protocol, or other analysis population. Because the described comparison involves measurements under both routes in the same participants, the handling of participants without complete data under both conditions would be important to understand. No such handling is reported. These omissions limit assessment of selective outcome reporting, the impact of missing observations, and the population to which any result would apply.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The adverse-event record lists 10 participants at risk for oral estradiol and 10 at risk for sublingual estradiol. It reports zero serious adverse events in each route group, zero other adverse events in each group, and zero deaths in each group. No serious adverse-event terms are listed.

These figures describe what is recorded for the listed risk groups; they do not establish that no adverse events could occur. In general, an absence of recorded events in a study does not establish the absence of risk, particularly when the number of participants is limited. The record does not give follow-up details for safety, event definitions beyond its categories, or information about systematic ascertainment, so the scope of these counts cannot be assessed further.

The enrollment figure is 11, but each route-specific risk group lists 10 participants. The reason is not reported in the registry record. Since the described design tests both routes in the same participants, the route groups should not be treated as two independent sets of people or their counts added together to infer a total number of unique participants.

These safety entries are separate from the primary pharmacokinetic endpoint. They do not provide evidence about longer-term outcomes or a general comparison of safety between routes. The registry record does not report a comparative safety analysis.

12. What the Result Does, and Does Not, Mean

The record documents a pilot study of oral and sublingual estradiol in transgender women, with a primary endpoint of maximum serum estradiol concentration over 8 hours. It describes oral administration first, a wash-out period of at least one week, and subsequent sublingual testing in the same participants. These details establish the question and basic sequence of measurements.

The record does not report the route-specific endpoint results. It therefore cannot establish whether maximum concentration differed between routes, which route had a higher observed value, or the magnitude and precision of any contrast. No clinical or statistical conclusion about the primary outcome can be drawn from the endpoint definition alone.

Even if a route difference were reported, a concentration difference would answer a limited pharmacokinetic question. It would not, by itself, establish a difference in symptoms, longer-term outcomes, or clinical benefit or harm. The registry summary discusses possible interest in sublingual administration, but the registered outcome is a blood concentration measure rather than a direct measure of those broader outcomes.

The design also constrains interpretation. The description indicates a fixed sequence, with the oral route preceding the sublingual route. Without reported randomization of sequence, a route contrast could be entangled with order or period effects. The record does not state whether statistical methods addressed these possibilities. It also does not report the endpoint analysis population or missing-data procedures.

The posted safety figures report no serious adverse events, other adverse events, or deaths among the participants listed at risk in either route group. Those counts are limited to the registry's recorded groups and do not establish absence of risk. The reason the risk-group counts differ from overall enrollment is not reported.

Accordingly, the registry supports a description of the study's design and intended measurement, but not a conclusion that one route is better, safer, or more effective. No medical advice should be inferred from these registry entries.

13. Why This Trial Matters Statistically

This study is statistically notable for asking a within-participant pharmacokinetic question in a population identified by the registry as transgender women. The same-participant structure can be useful because each participant may serve as a reference for their own measurements under the other route. In general, pairing can reduce the influence of stable between-person variation, provided that the measurements and analysis preserve the paired structure.

The fixed sequence is an important counterpoint. Oral administration is described first and sublingual testing follows a wash-out period of at least one week. When treatments are given in a fixed order, route and period are not independently randomized. General concerns include order effects and changes over time; the registry does not report whether these were assessed or addressed.

The primary endpoint also highlights the distinction between a clearly defined question and a reported result. The record names maximum serum estradiol concentration, gives units and a timeframe, and specifies mean and standard deviation. Yet it does not provide route-specific estimates or inferential results. Without those, readers cannot assess effect size or precision. Statistical interpretation depends on both a well-defined estimand and transparent reporting of the estimate, uncertainty, and analysis population.

The registry's pilot designation makes scope especially important. A small exploratory study can contribute useful information about measurements and study procedures, but the record does not report a sample-size justification. Planning illustrations, when used, are not observed power and do not replace uncertainty intervals around study results. No such primary result is reported in the registry record.

Finally, the registry lists multiple outcomes but does not report a multiplicity plan, missing-data methods, or analysis populations. These are not merely technical details: they affect how much confidence can be placed in selected findings and who those findings represent. Transparent reporting of these elements would help readers distinguish the intended comparison from conclusions the data can support.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry does not report the primary endpoint estimates, their variability, a route comparison, confidence intervals, or statistical test results. This is the central limitation for interpretation: the research question is specified, but the primary outcome cannot be evaluated from the posted record.

The design description indicates oral administration first and sublingual administration after a wash-out of at least one week. It does not describe randomized ordering. In general, a fixed order can make treatment route difficult to distinguish from period or order effects. The registry does not report whether the wash-out was assessed for each participant or whether other methods addressed potential carryover.

The enrollment figure is 11, whereas the safety groups list 10 participants at risk per route. The reason for the discrepancy is not reported in the registry record. The number included in the primary analysis, completeness of paired measurements, withdrawals, and exclusions are also not reported.

Other details needed to assess the analysis are absent: the statistical model or test, the endpoint derivation rule, missing-data handling, the analysis population, and any multiplicity procedure. The registry does not give a sample-size justification or a target for precision. These details should not be inferred from the endpoint definition or from general statistical practice.

The primary endpoint is a peak concentration over 8 hours, not a measure of longer-term exposure or clinical outcomes. The registry also does not provide a detailed safety follow-up description. Its zero event counts therefore have limited scope and do not establish that either route has no risk. These limitations arise from what is not reported in the registry record and should not be read as proof that the study did not collect additional information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Transgender Estradiol — NCT04036500.
• Registry record last updated 2025-04-11; status last verified 2025-04.
• Results first posted 2025-04-01.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04036500, “Transgender Estradiol,” is a completed EARLY PHASE1 study sponsored by the Medical College of Wisconsin. The official title is “Sublingual Estradiol Versus Oral Estradiol in Transgender Women.” The record lists enrollment of 11, a start date of 2019-09-23, and primary completion on 2020-07-13.

The described design is single-group and sequential: estradiol 1 mg orally, followed by a wash-out of at least one week and sublingual testing in the same participants. The primary outcome is maximum serum estradiol concentration in pg/mL over 8 hours, summarized by mean and standard deviation. A secondary outcome is the ratio of estrone to estradiol.

The registry lists 10 participants at risk in each route group and reports zero serious adverse events, zero other adverse events, and zero deaths in each group. Primary outcome estimates, analysis details, and the explanation for the enrollment and safety-group count difference are not reported in the registry record.