Why Some Transgender Women Get Too Much of a Good Thing
The path to feminizing hormone therapy is more complex than simply popping a pill.
For transgender women and transfeminine individuals, estrogen therapy is a cornerstone of medical transition, helping to align physical characteristics with gender identity. Yet beneath this seemingly straightforward process lies a delicate biological balancing act. Recent research reveals a surprising phenomenon: a significant number of patients on sublingual estradiol (where medication dissolves under the tongue) are ending up with hormone levels far beyond the therapeutic range. This discovery is prompting endocrinologists to rethink long-standing prescription practices and consider what makes each person's response to hormone therapy unique.
Medication dissolved under the tongue
Hormone levels beyond therapeutic range
Tailoring treatment to individual needs
To understand why sublingual dosing can lead to unexpectedly high hormone levels, we need to explore how different delivery methods behave in the body.
When you swallow an estradiol pill (oral administration), it travels through the digestive system and first passes through the liver, where a significant portion is metabolized and inactivated before reaching circulation. This "first-pass metabolism" reduces the immediate impact but creates a more sustained release 3 .
Sublingual administration bypasses this initial liver processing. By placing the medication under the tongue and allowing it to dissolve directly into the bloodstream, the absorption is both rapid and efficient. Studies show this method can produce peak estradiol concentrations three to five times higher than the same dose taken orally 3 .
One analysis found that a single 1 mg dose of sublingual estradiol could spike levels to an average of 144 pg/mL within hours, compared to just 35 pg/mL with an oral dose 3 .
However, this efficiency comes with a trade-off: the rapid decline of hormone levels after the initial peak. Sublingual estradiol has a short elimination half-life—just a few hours—compared to oral estradiol's 13-20 hour half-life 3 . This creates a hormonal rollercoaster rather than the steady state considered ideal for feminizing therapy.
In 2024, researchers conducted the first open-label randomized trial to directly compare how different estradiol regimens affect testosterone suppression in transgender women . This study provides crucial insights into the sublingual dosing question.
The research team divided 39 transgender women beginning hormone therapy into three treatment groups:
A single daily dose of 17-beta estradiol
The same total daily dose split into two administrations
Continuous delivery through skin patches
All participants also received spironolactone as an anti-androgen. Doses were adjusted monthly with the goal of suppressing testosterone to the cisgender female range (<50 ng/dL). Blood tests measured testosterone, estradiol, and estrone levels at multiple points over six months .
Contrary to what the researchers expected, the transdermal patch—providing a steady, continuous dose—suppressed testosterone more effectively and rapidly than either sublingual method .
The pulsed sublingual dosing, despite creating higher peak estradiol levels, showed no significant advantage for testosterone suppression. There was virtually no difference in effectiveness between once-daily and twice-daily sublingual dosing .
Additionally, the sublingual groups showed significantly higher estrone levels. Estrone is a weaker form of estrogen that can compete with the more potent estradiol at receptor sites, potentially reducing overall effectiveness .
| Administration Route | Testosterone <50 ng/dL Achievement | Key Findings |
|---|---|---|
| Transdermal Patch | Most rapid and effective suppression | Steady hormone delivery proved most efficient |
| Twice-Daily Sublingual | No significant advantage over once-daily | Pulsed dosing provided no extra benefit |
| Once-Daily Sublingual | Similar to twice-daily, less than transdermal | High peaks didn't improve suppression |
Table 1: Testosterone Suppression Across Different Estradiol Regimens
The clinical trial findings align with what providers observe in practice. Guideline-recommended dosing often doesn't produce expected hormone levels across different administration methods 6 .
One 2024 study found that with guideline-concordant parenteral (injection) estradiol doses, a striking 91% of patients had supratherapeutic levels at follow-up. Meanwhile, 70% of those using transdermal patches had subtherapeutic levels, suggesting our current dosing guidelines need refinement 6 .
Parenteral/Injection patients with supratherapeutic levels
Transdermal Patch patients with subtherapeutic levels
Oral Estradiol patients in therapeutic range
The implications extend beyond just hitting laboratory targets. Excessively high estrogen levels have been associated with increased risk of venous thromboembolism (blood clots) and other cardiovascular complications, particularly with oral formulations 1 . This makes finding the right dose and delivery method crucial for both effectiveness and safety.
| Administration Route | Mean Follow-up Level (pg/mL) | % in Therapeutic Range | % Subtherapeutic | % Supratherapeutic |
|---|---|---|---|---|
| Oral Estradiol | 168 pg/mL | 54% | 32% | 14% |
| Parenteral/Injection | 342 pg/mL | 9% | 0% | 91% |
| Transdermal Patch | 81.5 pg/mL | 20% | 70% | 13% |
Table 2: Real-World Estradiol Levels with Guideline-Concordant Dosing
Understanding how clinicians approach estrogen dosing requires familiarity with several key concepts and tools:
The primary, most potent form of estrogen used in gender-affirming therapy, available in oral, sublingual, transdermal, and injectable forms 1 .
The gold standard method for accurately measuring sex hormone levels, especially important for tracking the rapid fluctuations seen with sublingual dosing 8 .
A protein that binds to sex hormones in circulation, affecting their availability to tissues. SHBG levels can change in response to different estrogen formulations 8 .
Medications like spironolactone that block testosterone's effects or production. These work alongside estradiol to achieve feminization 1 .
| Component | Function/Role | Clinical Significance |
|---|---|---|
| Serum Estradiol Testing | Measures circulating estrogen levels | Guides dosing adjustments; targets typically 100-200 pg/mL |
| Testosterone Monitoring | Assesses effectiveness of suppression | Primary treatment target (<50 ng/dL) may matter more than estradiol |
| Timing of Blood Draws | Consistency relative to last dose | Critical for accurate interpretation, especially with sublingual |
| Liver Function Tests | Monitors potential medication stress | Particularly important with oral estrogen due to first-pass metabolism |
Table 3: Essential Components of Hormone Therapy Monitoring
The growing evidence about supratherapeutic levels with sublingual and injectable estradiol is shifting clinical perspectives. Rather than focusing solely on estradiol numbers, many experts now emphasize testosterone suppression as the primary treatment target 4 .
Recent large-scale analyses of nearly 10,000 individuals found that testosterone concentrations consistently correlated with key clinical variables, while estradiol levels showed surprisingly weak associations with treatment outcomes 4 . This suggests that chasing specific estradiol numbers may be less important than ensuring adequate testosterone suppression.
The takeaway for both patients and providers is that personalization trumps protocol. As one research team concluded, "These findings may suggest the need for revision of guideline-recommended estradiol doses" 6 . The route of administration, individual metabolism, and treatment goals all factor into finding the right regimen.
The discovery that sublingual estradiol frequently leads to supratherapeutic levels represents an important evolution in our understanding of gender-affirming care. What initially seemed like an efficient delivery method has revealed complex pharmacokinetics that require careful management.
As research continues, the field is moving away from one-size-fits-all dosing toward truly individualized treatment plans. The most exciting development may be the growing recognition that successful feminization therapy depends less on achieving arbitrary estradiol numbers and more on finding the right balance for each unique individual—considering their body's response, personal goals, and overall wellbeing.
For transgender women and transfeminine individuals navigating these decisions, this research underscores the importance of working with knowledgeable providers who understand these nuances and can tailor treatment accordingly. The path to effective, safe hormone therapy isn't about maximum dosing, but about finding the right equilibrium for both physical alignment and long-term health.