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An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People

By Sam | First published June 11, 2021 | Last modified March 30, 2024

Abstract / TL;DR

Despite being less well characterised in the medical literature than other formulations, sublingually administered estradiol has been used successfully by several gender clinics around the world. While there may be practical shortcomings associated with the sublingual route, clinical experience and best judgement would suggest it to be effective and affordable when dosed correctly. Sublingual administration of estradiol may be a useful alternative to oral administration for some transfeminine people and can be used for feminising hormone therapy instead.

Introduction

Although the most common way to administer medication in the form of pills or tablets is by the oral route, oral estradiol formulations can otherwise be taken sublingually or buccally (Kuhl, 2005). Sublingual administration refers to the placing of the pill or tablet under the tongue to dissolve and be absorbed into the bloodstream. Buccal administration is similar and refers to placing the medication between the cheek and gums, where it also quickly dissolves and is absorbed (Gass et al., 2004; Bartlett & Maarschalk, 2012).

Many transfeminine people wonder or ask questions on online forums about the sublingual route of administration for estradiol. Some of the most common queries are “What doses of sublingual estradiol should I take?”, “How often should I take sublingual estradiol?”, “Is sublingual estradiol better than oral estradiol?” and so on.

Previously, I reviewed the literature in a comparison of oral and transdermal estradiol (Sam, 2020a). Although many transfeminine people experiment with sublingual estradiol and its use appears to be commonplace among those who self-medicate with estrogens, I did not discuss sublingual or buccal routes of administration in this review. In part, the reason for this was because few studies exist concerning the use of sublingual estradiol compared to conventional and more widely used routes. This is likely also the reason that sublingual estradiol is not discussed in many clinical practice guidelines (Aly, 2020a). Moreover, I wanted to focus specifically on oral estradiol. Since the time of publication of that article, however, several new studies of sublingual estradiol in transfeminine people have been published. In light of this new information, and on account of the many questions asked by transfeminine people online, I believe an in-depth look at this route of administration is warranted. So this is intended to be an overview of the published medical literature regarding sublingual estradiol, with a specific focus on its use in transgender care, aiming to answer some of these questions.

It is of note that, although the sublingual and buccal administration are distinct routes of administration, they are very similar to each other in how they are performed and in their pharmacology (Perloff, 1950; Chandrasekhara et al., 2002). As such, although I have ostensibly chosen to make use of the term “sublingual” in this literature review, much of the content here is applicable to buccal administration of estradiol as well.

Pharmacology of Sublingual Estradiol

While sublingual estradiol has not been as widely used in clinical practice as oral estradiol and other formulations, a number of studies have examined its pharmacology. These studies include both samples of postmenopausal cisgender women and transfeminine people as well as other patient populations (Casper & Yen, 1981; Serhal & Craft, 1989; Deutsch, Bhakri, & Kubicek, 2015; Cirrincione et al., 2021). Both oral estradiol and oral estradiol valerate tablets can be taken sublingually (Serhal, 1990).

After the administration of a dose of oral estradiol, the medication is heavily metabolised and inactivated into estrogen conjugates by the liver (Kuhl, 2005). In turn, these metabolites are gradually converted back into estradiol, which serves to prolong its half life (to approximately 13–20 hours) (Stanczyk, Archer, & Bhavnani, 2013). In contrast to oral estradiol, sublingual estradiol does not pass extensively through the liver and is not significantly deactivated by hepatic metabolism into estrogen metabolites. Instead, sublingually administered estradiol is rapidly absorbed into the bloodstream and directly enters circulation. Consequently, sublingual estradiol has greater bioavailability than oral estradiol, meaning that lower doses are needed to achieve similar AUC estradiol levels (Kuhl, 2005) (Figures 1 and 2). This is an advantage of sublingual estradiol over oral estradiol, as it allows for lower doses to be used and for reduced medication costs.

Figures 1 and 2: Pharmacokinetics in different studies of a single 0.25 to 2 mg dose of micronised estradiol with oral administration (left) and sublingual or buccal administration (right). Sources: Burnier et al. (1981); Casper & Yen (1981); Fiet et al. (1982); Kuhnz, Gansau, & Mahler (1993); Price et al. (1997); Wiegratz et al. (2001); Wren et al. (2003); and Pickar et al. (2015). Dotted black lines represent approximately average integrated estradiol levels in premenopausal women (Verdonk et al., 2019).

Because accidental swallowing of some of the estradiol seems probable, the sublingual route is, most likely, actually a combination of sublingual and oral delivery of estradiol (Lobo, 1987; Kuhl, 2005). A preliminary report from an ongoing study of transfeminine people reported that a single 1 mg dose of sublingual estradiol caused an average rise in the level of estradiol up to a maximum of at least 179 pg/mL (657 pmol/L) within one to two hours of administration. In contrast, a peak concentration of just 36 pg/mL (130 pmol/L) was found with the same 1 mg dose administered orally (Doll et al., 2020). Thereafter, estradiol levels decreased rapidly. This response has also been found in other studies of postmenopausal women where a wide range of peak concentrations have been observed (Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). Estradiol levels are found to rapidly rise on the order of ten times that of the peak of oral estradiol, then rapidly decline with an elimination half-life of a few hours (Kuhl, 2005). Sublingual estradiol is somewhat analogous in this respect to intravenously administered estradiol, which also is associated with a rapid increase in estradiol levels and a very short elimination half-life following a dose (Kuhnz, Gansau, & Mahler, 1993). Another route of administration that is similar in this regard is intranasal administration (Devissaguet et al., 1999). Owing to the spikiness and short duration of sublingual estradiol, sublingual estradiol does not achieve as stable of concentrations as other formulations do. As such, this is a marked difference to other formulations of estradiol, such as oral estradiol, that produce much more stable hormone levels that do not fluctuate as much over the course of the day.

A range of estimates have been reported for the relative bioavailability of sublingual estradiol. One small randomised study of postmenopausal women found approximately 2.5-fold higher area-under-the-curve (AUC) levels of estradiol with sublingual estradiol than with the same doses of oral estradiol (Price et al., 1997). Other studies have reported relative bioavailability estimates for sublingual estradiol of up to five times that of oral estradiol (Pines et al., 1999). A study in marmoset monkeys found that the absolute bioavailability of sublingual estradiol was 10%; approximately twice that of conventional absolute bioavailability estimates of oral estradiol (5%, though with a wide range of 0.1 to 12%) (Kuhnz, Blode, & Zimmermann, 1993). Therefore, with respect to AUC levels of estradiol, the sublingual route appears to have between approximately two and five times higher estradiol levels compared to oral estradiol when given at the same doses. Based on these findings, approximate doses of sublingual estradiol for use in transfeminine hormone therapy can be derived (Table 1). It is of note that, at this time, the comparative potency of sublingual estradiol remains to be properly characterised due to a lack of research.

Table 1: Approximately comparable doses of estradiol (E2) and estradiol valerate (EV) administered by the oral and sublingual routes in terms of total estradiol exposure (Price et al., 1997; Pines et al., 1999):

 Low DoseModerate DoseHigh DoseVery-High Dose
Oral E22 mg/day4 mg/day8 mg/day10 mg/day
Sublingual E2a0.5–1 mg/day1–2 mg/day2–4 mg/day2.5–5 mg/day
Oral EV3 mg/day6 mg/day10 mg/day12 mg/day
Sublingual EVa0.75–1.5 mg/day1.5–3 mg/day2.5–5 mg/day3–6 mg/day

a Range calculated by dividing oral doses by two and four to reflect differences in absolute bioavailability and rounding to the nearest 0.25 mg. * Bioidentical estradiol has wide interindividual variation in its pharmacology and the effects of doses may vary significantly between individuals. EV has greater molecular weight and therefore contains less medication for the same amount/dose by weight. It should be noted that estimates for the relative bioavailability of EV are extrapolated from formulations with no valeric ester attached (i.e., E2).

Sublingually Administered Estradiol and Feminisation

The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions for its potential use of sublingual estradiol in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.

In contrast to oral and trandermal estradiol, no data exist describing the extent of feminisation with sublingual estradiol (Sam, 2020a). However, as discussed previously, oral and non-oral estradiol have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogondal girls (Rosenfield et al., 2005; Shah et al., 2014; Klaver et al., 2018; de Blok et al., 2021). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. The fact that several gender clinics have employed sublingual estradiol is also encouraging and suggests that sublingual estradiol is effective for inducing feminization (Deutsch, Bhakri, & Kubicek, 2015; Lim et al., 2019; Cirrincione et al., 2021). Nevertheless, as no studies have been conducted comparing the feminising efficacy of sublingual estradiol with objective measures, it is not possible to say for certain whether or not there is any difference in feminisation outcomes between oral and sublingual estradiol. Hopefully, studies in the future will shed more light on this.

Testosterone Suppressing Efficacy of Sublingually Administered Estradiol

Another question that might be raised by the short half-life of sublingual estradiol is how it might compare to more conventional routes of administration in terms of its ability to suppress testosterone and other androgens.

Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s, in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (Huggins & Hodges, 1941). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (Stege et al., 1996; Kohli, 2006; Sciarra et al., 2015). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Sublingual estradiol, on the other hand, has never been used as therapy for prostatic cancer and, consequently, no such data exist on the same scale to show the ability of sublingual estradiol in this capacity.

Recent data from some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (Leinung, Feustel, & Joseph, 2018; Pappas et al., 2020). Additionally, new data from around 900 men enrolled in the ongoing Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, show that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (<50 ng/dL [<1.7 nmol/L]) (Langley et al., 2021). However, because of the markedly different pharmacokinetics of sublingual estradiol, it is plausible that estradiol administered in this way might result in sub-par suppression at doses with similar AUC levels of estradiol. Put another way, sustained estradiol levels may be more efficacious with respect to testosterone suppression than the frequent and short-lived “spikes” in estradiol levels that occur with the sublingual route.

There is some weak evidence from pharmacological studies of estradiol that support this possibility. One line of evidence is that some studies of both sublingual and intravenous administration have reported rapid but limited suppression of the gonadotropins (follicle-stimulating hormone and luteinising hormone) in women despite sufficiently elevated estradiol levels for several hours (Tsai & Yen, 1971; Burnier et al., 1981; Casper & Yen, 1981; Hoon et al., 1993). These studies are low quality and indirect since testosterone suppression itself was not measured and they were performed in cisgender women. Another problem is that all were single dose studies and their findings may not translate to multiple dosing. It may be the case that full gonadotropin suppression becomes apparent with repeated physiologic doses of sublingual estradiol. Nevertheless, these studies might suggest a limited effect of sublingual estradiol to fully suppress gonadal function in transfeminine people without the use of excessive doses that would lead to greater health risks or the additional use of other antiandrogens.

It could be the case that monotherapy with sublingual estradiol may not be as effective at comparable doses to the typically employed doses in studies of prostatic cancer (e.g., two to four 100 μg/24 hours transdermal patches). Transdermal patches, gels and parenteral estradiol esters, such as estradiol valerate, injected intramuscularly or subcutaneously might therefore be more reliable choices for monotherapy regimens. On the other hand, sublingual estradiol has been studied in transfeminine people in combination with and without the low-dose use of the progestin medroxyprogesterone acetate (MPA) (Jain, Kwan, & Forcier, 2019). In this study, at least reasonably high rates of testosterone levels within the female range (<50 ng/dL [<1.7 nmol/L]) were achieved by the transfeminine people who took sublingual estradiol together with medroxyprogesterone acetate, showing that sublingual estradiol taken together with other antiandrogens (e.g., 10 mg/day cyproterone acetate) is very likely to be viable for achieving effective testosterone suppression (Aly, 2019).

Monitoring of Estradiol Levels with Sublingual Administration

A further consideration regarding the rapid changes in estradiol levels that occur with the use of sublingual estradiol is the relevance of monitoring of estradiol levels through bloodwork. Currently, consensus guidelines do not recommend a specific time for monitoring of the blood relative to the time of a last dose (Deutsch, 2016; Cheung et al., 2019; T’Sjoen et al., 2020). This may be in part due to practical reasons, or because there is currently no robust data from randomised controlled trials to guide the specifics of dosing in transgender hormone therapy (Haupt et al., 2020). Nevertheless, because estradiol levels vary so significantly with sublingual estradiol, knowledge of how long after the last dose blood was drawn is important to ensure proper interpretation of laboratory results.

For instance, measuring hormone levels just after a dose of sublingual estradiol has been taken might lead to the misinterpretation that levels of estradiol are excessively high and that one’s dosage should be reduced to achieve a more sensible concentration of estradiol in the blood. In reality, this would be a misunderstanding caused by the pharmacology of sublingual estradiol as the point of measurement would be right around the time when estradiol levels are most likely to be at their highest. These estradiol levels would not be indicative of the average amount of exposure, which is the more accurate measure of overall estrogenicity. Similarly, on the opposite end of the scale, drawing blood just before the administration of a new dose might lead to the belief that estrogen levels are too low and, consequently, lead to the use of excessive doses of estrogens. The latter misinterpretation may be more common among people unfamiliar with the pharmacology of sublingual estradiol as levels of estradiol only remain very high in the first few hours after a dose of sublingual estradiol has been taken before falling rapidly.

This oversight may also have implications in studies of sublingual estradiol. For instance, in the previously mentioned respective analysis of the use of sublingual estradiol for gender-affirming hormone therapy, the frequency of administration and time of measurement relative to the last dose were not specified in their results (Jain, Kwan, & Forcier, 2019). Although this data is much needed and is valuable to ongoing research to characterise sublingual estradiol in in transfeminine people, a significant problem is not knowing at what time estradiol levels were measured after the medication was administered. It is difficult to say much about the estradiol levels recorded in this study. Moreover, it is impossible to use this data to help derive equivalent doses of sublingual and oral estradiol.

A possible solution to the problem of rapidly changing hormone levels associated with the sublingual route might simply be to measure when estradiol levels are most likely to be closest to their average. In the case of sublingual estradiol, studies generally find this to be approximately four hours after the administration of a dose, although there is likely to be considerable variation between individuals (Kuhl, 2005). Nevertheless, this approach may give the most representative “snapshot” of overall estrogenic exposure and might help to avoid misleading laboratory data in users of sublingual estradiol.

Administration of Multiple Sublingual Doses Per Day

In order to compensate for the short half-life of sublingually administered estradiol, multiple doses of estrogens can be administered in smaller quantities per day to maintain hormone levels that are somewhat more consistent (Ahokas, Kaukoranta, & Aito, 1999).

In one study of premenopausal women with high-dose estrogen therapy, 2 mg of sublingual estradiol was administered three or four times per day (a total of 6–8 mg/day), resulting in significantly more stable hormone levels than would be expected with a single dose per day (Serhal & Craft, 1989). This was replicated in another study where estradiol was administered three to eight times per day (Ahokas et al., 2001). Conversely, a third study investigating low-dose buccal estradiol found little difference between the “steady-state” estradiol concentrations with a once-daily and twice-daily 0.25 mg dose of buccal estradiol over a 12 hour observation period (Wren et al., 2003). These findings may indicate that sublingual and buccal estradiol needs to be taken at least thrice per day in order to achieve concentrations of estradiol that are more stable.

For the reasons outlined in the subsections above, it would seem advantageous that transfeminine people using sublingual estradiol employ this approach and take sublingual estradiol in divided doses throughout the day; perhaps ideally at least three or four times per day. For instance, instead of taking a 2 mg dose every 24 hours, it would be better to take four 0.5 mg doses in the space of 24 hours (as evenly spaced as practical). Administering sublingual estradiol multiple times throughout the day might be less convenient, but is likely to provide at least somewhat more balanced estradiol levels and potentially better testosterone suppression. The administration of multiple doses every day could be regarded as optimal for the use of sublingually administered estradiol.

Safety and Tolerability

Unfortunately, as with the pharmacokinetics of sublingually and buccally estradiol, the published medical literature concerning the safety and tolerability of this route of administration leaves much to be desired. No long term safety data exist for sublingually administered estradiol in the same way that both oral and transdermal estradiol have been rigorously studied in menopausal women (Rovinski et al., 2018; CGHFBC, 2019).

Adverse Health Effects of Estrogens

With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (Kuhl, 2005; Aly, 2020b). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (Anderson et al., 2004; Mikkola et al., 2005). Although the absolute risk is low in the short-term, these are the most significant health concerns associated with gender-affirming hormone therapy.

A limited number of studies have assessed the effects of sublingually administered estradiol on the liver (Pines et al., 1999; Lim et al., 2019). These data found similar effects on lipids and cholesterol to other estrogens. One line of evidence that indicates sublingual estradiol has greater hepatic impact than other non-oral forms such as trandermal estradiol is the significantly greater quantities of estrone and estrone sulphate that are generated by this route; a marker of estrogenic exposure in the liver (Burnier et al., 1981; Cirrincione et al., 2021). Intense estrogenic activation in the liver is the mechanism by which non-oral estradiol induces a hypercoagulable state at high doses (Sam, 2020b; Sam, 2020c).

While a large body of research does exist concerning the short and long term health effects of estrogens, none of these studies have investigated sublingual or buccal estradiol (Oliver-Williams et al., 2019; Mishra et al., 2021). Given that oral estradiol has greater risks than non-oral estradiol, and that sublingual administration partially but not fully avoids first-pass metabolism, it may be the case that its own risk would be no higher than the risk observed with oral estradiol but no lower than the risk observed with non-oral routes. A retrospective cohort study in the United States found that the incidence of thromboembolism in transfeminine people with an average dose of 4 mg/day oral estradiol was approximately twice that of cisgender controls not taking hormone therapy after adjusting for confounders (HR 2.0, 95% CI 1.4–2.8 versus reference women) (Getahun et al., 2018). These increases in risks are much lower compared to regimens in transfeminine people in the past that included high doses of synthetic estrogens, but it’s important to remember that even such increases can significantly increase morbidity and mortality (Morimont, Dogné, & Douxfils, 2020). It would be advisable to limit doses of sublingual and buccal estradiol so that they are not excessive (i.e., <6 mg/day) in the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy.

Non-compliance

A practical obstacle to the use of sublingual estradiol in transfeminine people is that it may be highly inconvenient to have to administer doses thrice, four times or perhaps even more often throughout the duration of a single day. It has been found in observational studies that, in general, the number of prescribed medications and doses per day are positively associated with patient non-compliance and the number of missed doses (Jin et al., 2008; Toh et al., 2014). These findings are especially of relevance to transfeminine people as, in most cases, we require decades of hormone therapy. While missing one dose from time to time may be of little consequence, missing doses repeatedly could be more problematic.

In contrast to sublingual estradiol, the half-life of oral estradiol and transdermal gel is long enough to enable once-daily administration (Wiegratz et al., 2001; Potts & Lobo, 2005). In the case of transdermal patches and parenteral estradiol, these forms only have to be replenished every few days or after even longer intervals of time (Thurman et al., 2013; Wisner et al., 2015). Therefore, when considering the use of sublingual estradiol versus other forms, whether or not it would be practical or convenient to consistently take medication several times a day should probably also be an important consideration for transfeminine people. If not, then another formulation may be preferable for the person in question. This may be especially true for long term use.

Summary and Conclusions

There is much less research investigating sublingual and buccal estradiol than other forms of estrogen. These forms, namely oral and transdermal estrogens, are used in the alleviation of the menopause and for other indications that have historically been more widely used. As a result, they have received much more attention and characterisation than sublingual estradiol has for transfeminine hormone therapy. However, several recent studies have added to our knowledge of sublingual estradiol. Clinical practice guidelines for transgender care that have historically not discussed the use of sublingual estradiol may be adjusted accordingly if more information becomes available.

Sublingual estradiol is different in its pharmacology to other formulations. The main difference is that it is associated with a rapid rise and fall in estradiol levels. It has between two and four times the bioavailability of oral estradiol and hence provides the same total estradiol exposure at doses that are two to four times lower. This is a particular advantage because sublingual estradiol, therefore, is cheaper than oral estradiol, and the higher estradiol levels at the same dose may be helpful for testosterone suppression.

While no evidence exists to show or suggest that sublingual estradiol results in better or inferior feminisation to that experienced with other routes of administration, it is plausible that sublingual estradiol may to some degree result in less testosterone suppression at the same total estradiol exposure. Sublingual estradiol has, nonetheless, been shown to be effective with respect to testosterone suppression when paired with other antiandrogens. Care should be taken with sublingual estradiol when monitoring estradiol levels to ensure correct interpretation. In order to help minimise these potential problems, sublingual estradiol can be taken in multiple doses divided throughout the day.

The health risks of sublingual estradiol have not been quantified in large observational or randomised studies. Therefore, although the partial bypassing of the first pass through the liver is reassuring in this respect, its cardiovascular risk profile is unknown. Sublingual estradiol may be inconvenient and other formulations can be used instead if preferred, particularly for more long-term therapy.

Taken together, although much more research is clearly needed to properly characterise the route, sublingual estradiol may have a number of advantageous properties and may be a useful alternative to oral estradiol in transfeminine hormone therapy.

Updates

Update 1: New Sublingual Estradiol Studies (Added By Aly)

Since this article was first published, the following new relevant studies and papers on sublingual estradiol in transfeminine people have been published:

  • Doll, E., Gunsolus, I., Thorgerson, A., Tangpricha, V., Lamberton, N., & Sarvaideo, J. L. (2022). Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women. Endocrine Practice, 28(3), 237–242. [DOI:10.1016/j.eprac.2021.11.081]
    • Safer, J. D. (2022). Are the Pharmacokinetics of Sublingual Estradiol Superior or Inferior to Those of Oral Estradiol? Endocrine Practice, 28(3), 351–352. [DOI:10.1016/j.eprac.2021.12.018]
    • Sarvaideo, J., Doll, E., & Tangpricha, V. (2022). More Studies Are Needed to Establish the Safety and Efficacy of Sublingual Estradiol in Transgender Women. Endocrine Practice, 28(3), 353–354. [DOI:10.1016/j.eprac.2022.01.004]
  • Cortez, S., Moog, D., Lewis, C., Williams, K., Herrick, C., Fields, M., Gray, T., Guo, Z., Nicol, G., & Baranski, T. (2023). Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial. JMIR Research Protocols, 12, e53092. [DOI:10.2196/53092]
  • Jalal, E., & Baldwin, C. (2023). Supratherapeutic Estrogen Levels in Transgender Women Likely From Sublingual Estradiol. Journal of the Endocrine Society, 7(Suppl 1) [ENDO 2023 Abstracts Annual Meeting of the Endocrine Society], A1095–A1096 (abstract no. SAT391/bvad114.2062). [DOI:10.1210/jendso/bvad114.2062] [PDF]
  • Yaish, I., Gindis, G., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., & Tordjman, K. (2023). Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgender Health, 8(6), 485–493. [DOI:10.1089/trgh.2023.0022]
    • Gindis, G., Yaish, I., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., & Tordjman, K. (May 2023). Sublingual estradiol only, offers no apparent advantage over combined oral estradiol and cyproterone acetate, for Gender Affirming Hormone Therapy (GAHT) of treatment-naive transwomen: Results of a prospective pilot study. Endocrine Abstracts, 90 [25th European Congress of Endocrinology 2023, 13–16 May 2023, Istanbul, Turkey], 274–274 (abstract no. P182). [DOI:10.1530/endoabs.90.p182] [PDF]
    • Yaish, I., Gindis, G., Greenman, Y., Shefer, G., Buch, A., Arbiv, M., Moshe, Y., Sofer, Y., & Tordjman, K. M. (October 2023). Sublingual Estradiol Only, Compared To Combined Oral Estradiol And Cyproterone Acetate,Offers No Apparent Advantage For Gender Affirming Hormone Therapy (GHAT), In Treatment Naïve Transwomen: Results Of A Prospective Pilot Study. Journal of the Endocrine Society, 7(Suppl 1) [ENDO 2023 Abstracts Annual Meeting of the Endocrine Society], A1104–A1105 (abstract no. SAT409/bvad114.2080). [DOI:10.1210/jendso/bvad114.2080] [PDF]
  • Kariyawasam, N. M., Ahmad, T., Sarma, S., & Fung, R. (2024). Comparison of Estrone/Estradiol Ratio and Levels in Transfeminine Individuals on Different Routes of Estradiol. Transgender Health, online ahead of print. [DOI:10.1089/trgh.2023.0138]

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\ No newline at end of file +An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People - Transfeminine Science Link

An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People

By Sam | First published June 11, 2021 | Last modified August 7, 2025

Abstract / TL;DR

Sublingually-administered estradiol is an alternative route of administration to oral estradiol that has been used by a limited number of gender clinics around the world. We do not currently know if sublingual estradiol results in better, worse, or similar feminisation as other routes of administration because there is a paucity of clinical data in this area. There may be practical shortcomings associated with the sublingual route, however clinical experience suggest it to be effective and affordable when dosed correctly. Although much more research is clearly needed to properly characterise this route of administration, sublingual estradiol might have some advantageous properties and may be a useful alternative to oral estradiol for some transfeminine people.

Introduction

Although the most common way to administer medication in the form of pills or tablets is by the oral route, oral estradiol formulations can otherwise be taken sublingually or buccally (Kuhl, 2005). Sublingual administration is the administration of an oral pill or tablet by means of placing under the tongue to dissolve and be absorbed into the bloodstream. Buccal administration is similar and refers to placing the medication between the cheek and gums, where it also quickly dissolves and is absorbed (Gass et al., 2004; Bartlett & Maarschalk, 2012).

Many transfeminine people wonder or ask questions on online forums about the sublingual route of administration for estradiol. Some of the most common queries are “What doses of sublingual estradiol should I take?”, “How often should I take sublingual estradiol?”, “Is sublingual estradiol better than oral estradiol?” and so on.

Until very recently, published data about sublingual estradiol in transfeminine people was scarce, with only a very small number of relevant studies having considered it (eg: Jain, Kwan, & Forcier, 2019, Lim et al., 2019). Accordingly, most information about the sublingual route existed only in older studies of cisgender patient populations (Casper & Yen, 1981; Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). In the last few years, there has been a renewed interest in sublingual estradiol within the literature, specifically with an eye towards gender-affirming hormone therapy. Consequently, many high-level publications including recent clinical guidelines and reviews now make reference to the sublingual route (Coleman et al., 2022; Sudhakar et al., 2023; Grock, Reema, & Ahern, 2024).

It is of note that, although the sublingual and buccal administration are distinct routes of administration, they are very similar to each other in how they are performed and in their pharmacology (Perloff, 1950; Chandrasekhara et al., 2002). As such, although the term “sublingual” has been ostensibly used in this literature review, much of the content here is applicable to buccal administration of estradiol as well.

Pharmacology of Sublingual Estradiol

While sublingual estradiol is not as widely used in clinical practice as oral estradiol and other formulations, a number of studies have examined its pharmacology. These studies include both samples of postmenopausal cisgender women and transfeminine people as well as other patient populations (Casper & Yen, 1981; Serhal & Craft, 1989; Cirrincione et al., 2021; Doll et al., 2022; Kariyawasam et al., 2025). Both oral estradiol and oral estradiol valerate tablets can be taken sublingually (Serhal, 1990).

After the administration of oral estradiol, the medication is heavily metabolised and inactivated into estrogen conjugates by the liver (Kuhl, 2005). In turn, these metabolites are gradually converted back into estradiol, which serves to prolong its half life (to approximately 13–20 hours) (Stanczyk, Archer, & Bhavnani, 2013). In contrast to oral estradiol, sublingual estradiol does not pass as extensively through the liver. Therefore, it does not undergo deactivation into clinically insignificant estrogen metabolites. Sublingually administered estradiol is absorbed rapidly into the bloodstream where it directly enters circulation. Consequently, it has greater bioavailability than oral estradiol, meaning that lower doses are needed to achieve similar area-under-the-curve (AUC) estradiol levels (Kuhl, 2005) (Figures 1 and 2). This is an advantage of sublingual estradiol over oral estradiol, as it allows for the use of lower doses. This in turn might reduce medication costs.

Figures 1 and 2: Mean average pharmacokinetics in different studies of a single 0.25 to 2 mg dose of micronised estradiol with oral administration (left) and sublingual or buccal administration (right). Sources: Burnier et al. (1981); Casper & Yen (1981); Fiet et al. (1982); Kuhnz, Gansau, & Mahler (1993); Price et al. (1997); Wiegratz et al. (2001); Wren et al. (2003); and Pickar et al. (2015). Dotted black lines represent approximately average integrated estradiol levels in premenopausal women (Verdonk et al., 2019).

Because accidental swallowing of some of the estradiol seems probable, the sublingual route is, most likely, actually a combination of sublingual and oral delivery of estradiol (Lobo, 1987; Kuhl, 2005). A small pharamcokinetics study of transfeminine people reported that a single 1 mg dose of sublingual estradiol caused an average rise in the level of estradiol up to an average of 144 pg/mL (529 pmol/L) within one to two hours of administration. In contrast, a peak concentration of just 35 pg/mL (128 pmol/L) was found with the same dose of 1 mg administered orally (Doll et al., 2022). Thereafter, estradiol levels decreased rapidly. In another study, it was found that mean estradiol levels measured at any given point were 613 pmol/L (167 pg/mL) on sublingual estradiol (Kariyawasam et al., 2025). In this study, a wide range of doses were used and hence it is not possible to ascertain much about dose-specific peak concentrations. Similar findings have been reported in other studies of postmenopausal women, although a wide range of peak concentrations have been observed (Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). Estradiol levels are found to rapidly rise on the order of about five to ten times that of the peak of oral estradiol, then rapidly decline, with an elimination half-life of only a few hours (Kuhl, 2005). Sublingual estradiol is somewhat analogous in this respect to intravenously administered estradiol, which also shows a rapid increase in estradiol levels and a very short elimination half-life (Kuhnz, Gansau, & Mahler, 1993). Another route of administration that is similar in this regard is intranasal administration (Devissaguet et al., 1999). Owing to the short half-life elimination of sublingual estradiol, it does not achieve as stable concentrations as other formulations do. This is a marked difference to other routes, such as oral estradiol, that produce much more stable hormone levels and that do not fluctuate as much over the course of the day. All these differences by themselves do not necessarily mean that sublingual estradiol is superior or inferior to oral estradiol (Safer, 2022; Sarvaideo, Doll, & Tangpricha, 2022). Nevertheless, they should be kept in mind when considering findings from relevant studies.

A range of estimates have been reported for the relative bioavailability of sublingual estradiol. One small randomised study of postmenopausal women found approximately 2.5-fold higher AUC levels of estradiol with sublingual estradiol than with the same doses of oral estradiol (Price et al., 1997). Other studies have reported relative bioavailability estimates for sublingual estradiol of up to five times that of oral estradiol (Pines et al., 1999). A study in marmoset monkeys found that the absolute bioavailability of sublingual estradiol was 10%; approximately twice that of conventional absolute bioavailability estimates of oral estradiol (5%, though with a wide range of 0.1 to 12%) (Kuhnz, Blode, & Zimmermann, 1993). Therefore, with respect to AUC levels of estradiol, the sublingual route appears to have between approximately two and five times higher estradiol levels compared to oral estradiol when given at the same doses. Based on these findings, approximately equivalent doses of sublingual estradiol can be derived (Table 1). It is notable that due to substantial interindividual variation in the metabolism of different forms of estradiol, these relative doses are unlikely to correspond to one another on a person-by-person basis. Measurement of circulating estradiol concentrations should always be used to guide dose titration.

Table 1: Approximately comparable doses of estradiol (E2) and estradiol valerate (EV) administered by the oral and sublingual routes in terms of total estradiol exposure (Price et al., 1997; Pines et al., 1999):

 Low DoseModerate DoseHigh DoseVery-High Dose
Oral E22 mg/day4 mg/day8 mg/day10 mg/day
Sublingual E2a0.5–1 mg/day1–2 mg/day2–4 mg/day2.5–5 mg/day
Oral EV3 mg/day6 mg/day10 mg/day12 mg/day
Sublingual EVa0.75–1.5 mg/day1.5–3 mg/day2.5–5 mg/day3–6 mg/day

a Range calculated by dividing oral doses by two and four to reflect differences in absolute bioavailability and rounding to the nearest 0.25 mg. * Bioidentical estradiol has wide interindividual variation in its pharmacology and the effects of doses are likely to vary significantly between individuals. EV has greater molecular weight and therefore contains less medication for the same amount/dose by weight. It should be noted that estimates for the relative bioavailability of EV are extrapolated from formulations with no valeric ester attached (i.e., E2).

Administration of Multiple Sublingual Doses Per Day

In order to compensate for the short half-life of sublingually administered estradiol, multiple doses of estrogens can be administered in smaller quantities per day to maintain hormone levels that are somewhat more consistent (Ahokas, Kaukoranta, & Aito, 1999; Yaish et al., 2023a; Cortez et al., 2024).

In one study of premenopausal women with high-dose estrogen therapy, 2 mg of sublingual estradiol was administered three or four times per day (a total of 6–8 mg/day), resulting in significantly more stable hormone levels than would be expected with a single dose per day (Serhal & Craft, 1989). This was replicated in another study where estradiol was administered three to eight times per day (Ahokas et al., 2001). Conversely, a third study investigating low-dose buccal estradiol found little difference between the “steady-state” estradiol concentrations with a once-daily and twice-daily 0.25 mg dose of buccal estradiol over a 12 hour observation period (Wren et al., 2003). These findings may indicate that sublingual and buccal estradiol needs to be taken at least thrice per day in order to achieve concentrations of estradiol that are more stable.

It would seem advantageous for transfeminine people using sublingual estradiol that sublingual estradiol is taken in divided doses throughout the day; perhaps ideally at least three or four times per day. For instance, instead of taking a 2 mg dose every 24 hours, it would be better to take four 0.5 mg doses in the space of 24 hours (as evenly spaced as practical). Administering sublingual estradiol multiple times throughout the day might be less convenient, but is likely to provide at least somewhat more balanced estradiol levels. The administration of multiple doses every day could be regarded as optimal for the use of sublingually administered estradiol.

Sublingually Administered Estradiol and Feminisation

The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions relating to its use in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.

In contrast to oral and trandermal estradiol, limited data exist describing the extent of feminisation with the sublingual route (Safer, 2022). A non-randomised study found that self-assessed Tanner stage after 6 months of treatment did not appear to be different in users of sublingual estradiol monotherapy as compared to users of oral estradiol plus 10 mg/day cyproterone acetate (Yaish et al., 2023a; Yaish et al., 2023b). However, since breast development itself was not measured objectively, these particular data are low-quality and prevent definitive conclusions either way about the superiority or inferiority of sublingual estradiol. The same study group reported that although there were similar increases in gynoid fat in the two arms, the oral estradiol group did show an increased amount of android fat as compared to the sublingual group (Yaish et al., 2025). On the other hand, a further complication of this study is the possible confounding by lack of concomitant antiandrogen therapy in the sublingual arm (Ruggles & Cheung, 2024; Yaish et al., 2024). Notably, progestogens like cyproterone acetate have been shown to be associated with weight gain (Lopez et al., 2016). This could explain the difference in android fat accumulation.

Oral estradiol and other non-oral forms of estradiol (such as transdermal administration) have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogonadal girls (Rosenfield et al., 2005; Shah et al., 2014; Klaver et al., 2018; de Blok et al., 2021, Tebbens et al., 2022). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. However, the use of supraphysiological doses of estrogens from the onset of therapy may stunt breast development and reduce final breast size in transfeminine people (Boogers et al., 2025). Because the use of sublingual estradiol results in estradiol concentrations that routinely achieve the supratherapeutic range, it is possible that this could have deleterious effects on breast development.

The fact that several gender clinics have employed sublingual estradiol for some time is encouraging (Deutsch, Bhakri, & Kubicek, 2015; Lim et al., 2019; Cirrincione et al., 2021). Nevertheless, as there is very limited data comparing the feminising efficacy of sublingual estradiol with objective measures, no firm conclusions about any differences in feminisation outcomes between sublingual estradiol and other routes of administration can currently be drawn. Hopefully, studies in the future will shed more light on this.

Testosterone Suppressing Efficacy of Sublingually Administered Estradiol

Another question that might be raised by the short half-life of sublingual estradiol is how it might compare to more conventional routes of administration in terms of its ability to suppress testosterone and other androgens.

Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (Huggins & Hodges, 1941). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (Stege et al., 1996; Kohli, 2006; Sciarra et al., 2015). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Since sublingual estradiol has never been used to treat prostatic cancer, no such data exist to show the ability of sublingual estradiol in this capacity.

Some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) or slightly higher from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (Leinung, Feustel, & Joseph, 2018; Pappas et al., 2020; Misakian et al., 2025). Additionally, the Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, showed that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (<50 ng/dL [<1.7 nmol/L]) (Langley et al., 2021). However, because sublingual estradiol differs in its pharmacokinetics to other forms of estradiol, it is plausible that this route of administration might result in sub-par suppression at doses with similar concentrations of estradiol.

A few studies have reported the extent of testosterone suppression under sublingual estradiol in transfeminine people. In a randomised controlled trial (RCT) comparing once-daily and twice-daily administration of 2 mg sublingual estradiol to 0.1 mcg/day transdermal estradiol with and without spironolactone, both of the sublingual arms were found to result in inferior testosterone suppression at 1-month and 6-month follow-up (Cortez et al., 2023; Cortez et al., 2024). The authors hypothesised that this could be due to the ability of high concentrations of estrone, which were seen with sublingual estradiol, to inhibit cooperative binding of the estrogen receptor. However, this notion is contradicted by studies comparing oral and transdermal administration of estradiol which have reported no difference in the ability of these formulations to suppress testosterone at equivalent doses (SoRelle et al., 2019; Salakphet et al., 2022; Slack et al., 2025). This is in spite of the large amount of estrone also known to be generated from oral estradiol. Another study of transfeminine people found that sublingual estradiol at a dose of 0.5 mg administered four times daily was able to suppress testosterone as well as oral estradiol in combination with low-dose cypoterone acetate (Yaish et al., 2023a; Yaish et al., 2023b). The use of the four times daily dosing regimen in this study may account for the difference in findings between these two studies in the ability to suppress testosterone. Sublingual estradiol has been studied in transfeminine people in combination with and without the low-dose use of the progestin medroxyprogesterone acetate (MPA) (Jain, Kwan, & Forcier, 2019). In this study, high rates of suppressed testosterone levels (ie: <50 ng/dL [<1.7 nmol/L]) were achieved by the transfeminine people who took sublingual estradiol with medroxyprogesterone acetate, showing that sublingual estradiol taken together with progestogens such as cyproterone acetate is viable for achieving effective testosterone suppression.

A possibility supported by some evidence from pharmacological studies of estradiol is that sustained estradiol levels may be more efficacious with respect to testosterone suppression than the frequent and short-lived peaks in estradiol concentrations that occur with the sublingual route. In some studies of both sublingual and intravenous administration, limited suppression of the gonadotropins (follicle-stimulating hormone and luteinising hormone) have been reported in women despite sufficiently elevated estradiol levels for several hours (Tsai & Yen, 1971; Burnier et al., 1981; Casper & Yen, 1981; Hoon et al., 1993). These studies are low quality and indirect since testosterone suppression itself was not measured and they were performed in cisgender women. Another problem is that all were single dose studies and their findings may not translate to multiple dosing. Nevertheless, these studies might suggest a mechanism by which sublingual estradiol is unable to fully suppress gonadal function in transfeminine people without the use of excessive doses that would lead to greater health risks or the additional use of other antiandrogens.

For the reasons above, transdermal patches, gels and parenteral estradiol esters, such as estradiol valerate, injected intramuscularly or subcutaneously are probably more reliable choices for estradiol monotherapy regimens. If sublingual estradiol is used as a single agent therapy, it would seem reasonable to suggest the use of many divided doses taken throughout the day, as this is probably more likely to be efficacious. Nevertheless, sublingual estradiol appears to be more effective in terms of testosterone suppression when used with concomitant antiandrogens.

Monitoring of Estradiol Levels with Sublingual Administration

A further consideration regarding the rapid changes in estradiol levels that occur with the use of sublingual estradiol is the relevance of monitoring of estradiol levels through bloodwork. Currently, consensus guidelines do not recommend a specific time for monitoring of the blood relative to the time of a last dose (Cheung et al., 2019; T’Sjoen et al., 2020; Coleman et al., 2022). This may be in part due to practical reasons, or because until very recently there were currently no robust data from randomised controlled trials to guide the specifics of dosing in transgender hormone therapy (Haupt et al., 2020). Nevertheless, because estradiol levels vary so significantly with sublingual estradiol, knowledge of how long after the last dose blood was drawn is important to ensure proper interpretation of laboratory results.

For instance, measuring hormone levels just after a dose of sublingual estradiol has been taken might lead to the misinterpretation that levels of estradiol are excessively high and that one’s dosage should be reduced to achieve a more sensible concentration of estradiol in the blood. In reality, this would be a misunderstanding caused by the pharmacology of sublingual estradiol as the point of measurement would be right around the time when estradiol levels are most likely to be at their highest. These estradiol levels would not be indicative of the average amount of exposure, which is the more accurate measure of overall estrogenicity. Similarly, on the opposite end of the scale, drawing blood just before the administration of a new dose might lead to the belief that estrogen levels are too low and, consequently, lead to the use of excessive doses of estrogens. The latter misinterpretation may be more common among people unfamiliar with the pharmacology of sublingual estradiol as levels of estradiol only remain very high in the first few hours after a dose of sublingual estradiol has been taken before falling rapidly.

A possible solution to the problem of rapidly changing hormone levels associated with the sublingual route might simply be to measure when estradiol levels are most likely to be closest to their average. In the case of sublingual estradiol, studies generally find this to be approximately four hours after the administration of a dose, although there is likely to be considerable variation between individuals (Kuhl, 2005). Nevertheless, this approach may give the most representative “snapshot” of overall estrogenic exposure and might help to avoid misleading laboratory data in users of sublingual estradiol.

Safety and Tolerability

Unfortunately, no long term safety data exist for sublingually administered estradiol in the same way that both oral and transdermal estradiol have been rigorously studied in menopausal women (Rovinski et al., 2018; CGHFBC, 2019). The published medical literature concerning the safety and tolerability of this route of administration leaves many questions unanswered.

Adverse Health Effects of Estrogens

With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (Kuhl, 2005). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (Anderson et al., 2004; Mikkola et al., 2005). Although the absolute risk is low in the short-term, these are the most significant health concerns associated with gender-affirming hormone therapy.

A retrospective cohort study in the United States found that the incidence of thromboembolism in transfeminine people with an average dose of 4 mg/day oral estradiol was approximately twice that of cisgender controls not taking hormone therapy after adjusting for confounders (HR 2.0, 95% CI 1.4–2.8 versus reference women) (Getahun et al., 2018). These increases in risks are much lower compared to regimens in transfeminine people in the past that included high doses of synthetic estrogens, however even such increases can significantly increase morbidity and mortality (Morimont, Dogné, & Douxfils, 2020). A 2021 meta-analysis reported an absolute incidence of VTE of 2% in transfeminine people receiving gender-affirming hormone therapy, although with significant between-study heterogeneity (Totaro et al., 2021).

Some studies have assessed the effects of sublingually administered estradiol on the liver (Pines et al., 1999; Lim et al., 2019). These data found similar effects on lipids and cholesterol to other estrogens. One line of evidence that indicates sublingual estradiol has greater hepatic impact than other non-oral forms such as trandermal estradiol is the significantly greater quantities of estrone and estrone sulphate that are generated by this route; a marker of estrogenic exposure in the liver (Burnier et al., 1981; Cirrincione et al., 2021). Intense estrogenic activation in the liver is the mechanism by which non-oral estradiol induces a hypercoagulable state at high doses (Kuhl, 2005). While a large body of research does exist concerning the short and long term health effects of estrogens, none of these studies have investigated sublingual or buccal estradiol (Oliver-Williams et al., 2019; Mishra et al., 2021). Given that oral estradiol has greater risks than non-oral estradiol, and that sublingual administration partially but not fully avoids first-pass metabolism, it may be the case that its own risk would be somewhere between the risk observed with oral estradiol and the risk observed with other conventional non-oral routes (such as transdermal estradiol). However, an ongoing prospective study reported that use of sublingual estradiol alone resulted in less favourable outcomes on some markers of coagulation in the liver as compared to oral estradiol and cyproterone acetate (Bar et al., 2024). These data are indirect, however could suggest that contrary to theoretical expectations, sublingual estradiol might be closer or even less favourable than the risk profile of oral estradiol.

Other adverse effects of estradiol include breast cancer and gallbladder disease. These risks are believed to be dose-dependent (Cummings et al., 1999; Liu et al., 2008). However, as with cardiovascular and thromboembolic complications, no data exist to describe the long-term risk in these other areas with sublingual formulations. In the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy, it would be advisable to limit doses of sublingual and buccal estradiol so that they are not excessive (i.e., <6 mg/day) (Jalal & Baldwin, 2023).

Non-compliance

A practical obstacle to the use of sublingual estradiol in transfeminine people is that it may be highly inconvenient to have to administer doses thrice, four times or perhaps even more often throughout the duration of a single day. It has been found in observational studies that, in general, the number of prescribed medications and doses per day are positively associated with patient non-compliance and the number of missed doses (Jin et al., 2008; Toh et al., 2014). These findings are especially of relevance to transfeminine people as, in most cases, we require decades of hormone therapy. While missing one dose from time to time may be of little consequence, missing doses repeatedly could be more problematic. Despite this, sublingual estradiol has been used in studies of transfeminine people where it has been administered up to four times daily (Yaish et al., 2023a).

In contrast to sublingual estradiol, the half-life of oral estradiol and transdermal gel is long enough to enable once-daily administration (Wiegratz et al., 2001; Potts & Lobo, 2005). In the case of transdermal patches and parenteral estradiol, these forms only have to be replenished every few days or after even longer intervals of time (Thurman et al., 2013; Wisner et al., 2015). Therefore, when considering the use of sublingual estradiol versus other forms, whether or not it would be practical or convenient to consistently take medication several times a day should probably also be an important consideration for transfeminine people. If not, then another formulation may be preferable for the person in question. This may be especially true for long term use.

Summary and Conclusions

Sublingual estradiol is different in its pharmacology to other routes. The main difference is that it is associated with a rapid rise and fall in estradiol levels. It has between two and four times the bioavailability of oral estradiol and hence provides the same total estradiol exposure at doses that are two to four times lower. This could be a particular advantage because sublingual estradiol, therefore, is cheaper than oral estradiol.

There is much less research investigating sublingual estradiol than other forms of estrogen. These forms, such as oral and transdermal estrogens, are widely used in the alleviation of the menopause and for other indications. Consequently, they have received much more attention and characterisation than sublingual estradiol has for transfeminine hormone therapy. However, studies are beginning to add our knowledge of sublingual estradiol. Clinical practice guidelines for transgender care, which historically did not make reference to the use of sublingual estradiol, have now begun to discuss it.

The evidence is inconclusive regarding whether sublingual estradiol results in better, worse, or the same feminisation when compared with other routes of administration. However, it is plausible that the supra-physiologic levels of estradiol that frequently occur with sublingual estradiol could be detrimental to breast development. It also seems that sublingual estradiol could result in lesser testosterone suppression when used as a single agent therapy as compared to other routes. Sublingual estradiol has, nonetheless, been shown to be effective with respect to testosterone suppression when paired with other antiandrogens. Care should be taken with sublingual estradiol when monitoring estradiol levels to ensure correct interpretation. In order to help minimise these potential problems, sublingual estradiol can be taken in multiple doses divided throughout the day.

The health risks of sublingual estradiol have not been quantified in large observational or randomised studies. Therefore, although the first pass effect in the liver is partially avoided, the cardiovascular risks associated with long-term sublingual estradiol remain unknown. Sublingual estradiol may also be inconvenient and other formulations can be used instead if preferred, particularly for more long-term therapy.

Taken together, although much more research is clearly needed to properly characterise sublingual estradiol in transfeminine hormone therapy, it might have some advantageous properties and may be a useful alternative to oral estradiol.

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Analysis of Studies Assessing the Risk of Thromboembolism with Transfeminine Hormone Therapy

By Sam | First published May 19, 2020 | Last modified October 5, 2020

Notice: This page was originally posted as a thread on social media and has not been properly or fully revised since being moved to Transfeminine Science.

Abstract / TL;DR

See the Summary of Evidence section at the end of the article.

Background

Venous thromboembolism (VTE) is the umbrella term that includes deep vein thrombosis (DVT) and pulmonary embolism (PE) (Tritschler et al., 2018). A thrombosis is a blood clot that forms in a vein; usually within the leg, whereas an embolism is a thrombosis that has broken off from the original site and blocked the flow of blood inside a blood vessel. VTE can cause permanent damage to organs such as the lungs or even lead to death (The Lancet Haematology, 2015). Thankfully, the incidence of thromboembolism is relatively low in the general population. However, age is an important independent risk factor for VTE (Silverstein et al., 1998). Men and women under the age of 50 have less than a 100 cases per 100,000 people per year incidence of VTE. But thereafter, risk increases rapidly with age. By the age of 80, men have an incidence of approximately 1,000 cases per 100,000 people per year.

Thromboembolism is of significance to the field of gender-affirming hormone therapy (GAHT) as estrogens and some progestogens are associated with an increased incidence of VTE. A 2018 meta-analysis of clinical trials, case-control and cohort studies of menopausal hormone therapy (MHT) found that oral but not non-oral estradiol at low doses is associated with mildly greater risk of VTE (Rovinski et al., 2018). This finding has been attributed to the disproportionate amount of liver exposure that occurs with the oral route of administration (Kuhl, 2005). However, the doses of estrogens used in MHT are usually much lower than those used in GAHT. Moreover, high doses of progestins, such as cyproterone acetate, are commonly used in clinical practice to suppress testosterone levels to the female range. As such, the incidence of VTE that occurs with estrogen therapy in GAHT is, overall, likely to be greater than that observed in studies of postmenopausal women.

Analysis

Previously, I investigated thromboembolic and cardiovascular toxicity with high dose parenteral estrogen therapy in the treatment of prostate cancer (Sam, 2020). I thought it would be interesting to perform an investigation into the risk of these side effects in transgender women. Additionally, I wanted to see if any association could be found between different types of regimens.

Many studies have quantified the risk of VTE in transfeminine people with gender-affirming hormone therapy (Asscheman, Gooren & Eklund, 1989; van Kesteren et al., 1997; Dittrich et al., 2005; De Cuypere et al., 2005; Ott et al., 2010; Mueller et al., 2011; Seal et al., 2012; Wierckx et al., 2013; Wierckx et al., 2014; Gava et al., 2016; Arnold et al., 2016; Getahun et al., 2018; Nota et al., 2019). Unfortunately, a recurring problem in many of these studies is the extremely low number of patient follow-up years. Because studies with small numbers of follow-up years may significantly underestimate or overestimate the prevalence of adverse effects, they have poor statistical precision. Therefore, it makes it difficult to draw conclusions from their findings. In my own analysis, I excluded any study that had fewer than 1,000 patient follow-up years. Consequently, there were seven studies available for analyses.

Of the seven remaining studies, all but one were retrospective. In four studies, cyproterone acetate was used in all or most patients, while other antiandrogens were used in most or all of the patients in the other three studies. In the first three studies, most or all of the patient follow-up was for therapy with non-bioidentical estrogens. Bioidentical estrogens were used in the latter four studies. For each study, I calculated the crude incidence rate. Using data from a 25-year population study (Silverstein et al., 1998), I was then able to calculate the incidence rate ratio (IRR) with a 95% confidence interval relative to age-matched cisgender men and women for each study and for therapy with and without cyproterone acetate and for the type of estrogen (non-bioidentical or bioidentical) using the method described here.

In Getahun et al. (2018), a much different methodology and definition of VTE to other studies was used. Therefore, the number of VTE cases reported was much higher than what would have been expected with the methodology in Silverstein et al. (1998). I used the hazard ratios (HR) as reported in the original paper in order to avoid presenting an IRR vastly higher than what was really observed. Therefore, my analysis is limited by this discrepancy.

A summary of the details for each study can be found here.

The results of these analysis are presented below.

Figure 1: Incidence of VTE in studies of GAHT with more than 1,000 follow-up years relative to cisgender women.
Figure 2: Incidence of VTE in studies of GAHT with more than 1,000 follow-up years relative to cisgender men.
Figure 3: Incidence of VTE grouped by association with different GAHT regimens.

Summary of Evidence

Many retrospective and prospective studies have aimed to quantify the risk of thromboembolism with gender-affirming hormone therapy. In the studies with the best statistical precision, feminising hormone therapy with estrogens and antiandrogens is associated with a modest to strong increase in the risk of thromboembolism relative to age-matched cisgender men and women. However, the most severe increase was observed only with ethinylestradiol; a non-bioidentical estrogen. Non-bioidentical estrogens are known to have a much greater influence on the coagulation system than bioidentical estrogens and ought to be avoided in feminising hormone therapy (Swee et al., 2019).

Perhaps the most interesting takeaway from this analysis is that the use of cyproterone acetate in gender-affirming hormone therapy seems to be responsible for most of the increased risk that occurs with conventional regimens. This may be both reassuring and concerning at the same time. On the one hand, this indicates only a modest increase in risk when other antiandrogens are used. However, cyproterone acetate is widely used as an antiandrogen in clinical practice and by transfeminine people who self-medicate.

Cyproterone acetate was used in these studies at doses of 50 to 100 mg/day. However, there is mounting evidence that much lower doses are maximally effective for testosterone suppression, while higher doses have greater risk of harm (Aly, 2019; Aly, 2020). The finding that CPA appears to be the main culprit for pronounced increase in the risk of thromboembolism exemplifies the need for the lowest possible doses to be used. Using lower doses may confer a lower increase in risk. Moreover, it is reasonable that the use of CPA as an antiandrogen in older individuals be avoided (ie: those over the age of 50 and who are at much higher risk of VTE and other serious adverse effects). Other antiandrogens such as bicalutamide, spironolactone or LHRH analogues are very likely much safer and appropriate choices for GAHT in high risk groups of transgender people.

It should be said that my analysis is limited (as described in the Analysis section of this article). Also, my work has not been peer-reviewed by clinicians and researchers and has not been published professionally in a medical journal.

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z05ItNY+e&on;gQdbea*8AA4w&TC*xR2Rv~bfS=0%O-gO5s`d?pOC)(`ISPrt$~rV5 z4EQxq{jXT<7# z2-`mFRLgcxH$z*&23VWmn)0ex#>(30o@Yp~USG#W-VNsZcZq zwa#RYS$)-2(07NyRVj2RjL9g5xJ7e?tel@W=k5RypZnO2{TO}G$ue35dkMC^s7Wtx z{7~tX&)hSFKd0GcES0oG`awR%7Eg$LK-fXvN|)w4=Ob0`$-G)1XwQQ{Fjb40(z6ot zQV8!;xDVo-a|$tlV<*y4+enV7YE}voL8XHnjv*Eb_b-Z_4wFj7Lqzdx}A6HjadW_QqOX^crxJ@Z!RTmjLB2v@GjE5l{fLpZRwX#>Pt*Mdym+~$)WxP}l} zL5GlYk>o979+FjH58G*Ki<{Pp=@6ODtg+PY{_HKIlW&8Gkvcpud{1Uy@wPV#56N2S z7@YdaHxSQ`l=fj}eHG?HFN}-wJG|`i;e~94R|e`bh#}f`=MtfvZG(V}4_^gn1D&jp zLw3YHHuAQ_$Q#DUU z$I@RZXUVq#tV8{>XGx#ydlo<(P65VqW*eejf>Pv4$B|UjlFJi%+1Ws^IIJ2*B|Xfa z#enO+eCr|UtG4j{z@C4sMz!)!dj`s0bm{^nlObW%6Egjop|hI_+^wpn-$&B-T+I&z z1bQW!t!|%{ch%-Oy{H`&Cp#o0%=5x?(NN;u7k{nCL4>-F-=;q%{ma`T;M$$KAO$$y zh1f5g4!~CUXQq(Q*tn}Ttm@O(Ra4RTIpvXW|qZ{k!++Z%iqXA*WF00 z_rp7|JK@Bstw;ldQTSn@0JhOrks-X9F}C(=Wqpg!or8_^>{$^s9*wI`6GfvIal_MGp;y%T zCgn7_sm?5#7Ytiq8KCg|I&=+Tp`a19UvxLkXoGbYKKmR80Ff)|7OQBXDkJekyll2025-07-30T04:25:49-07:00https://transfemscience.org/feed-posts.xmlTransfeminine ScienceTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine Science \ No newline at end of file +Jekyll2025-08-08T04:26:08-07:00https://transfemscience.org/feed-posts.xmlTransfeminine ScienceTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine Science \ No newline at end of file diff --git a/transfemscience.org/feed.xml b/transfemscience.org/feed.xml index ae262487..0e2c2159 100644 --- a/transfemscience.org/feed.xml +++ b/transfemscience.org/feed.xml @@ -1,4 +1,4 @@ -Jekyll2025-07-30T04:25:49-07:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth +Jekyll2025-08-08T04:26:08-07:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth @@ -2464,33 +2464,33 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome
  • Yáñez, J. A., Remsberg, C. M., Sayre, C. L., Forrest, M. L., & Davies, N. M. (2011). Flip-flop pharmacokinetics–delivering a reversal of disposition: challenges and opportunities during drug development. Therapeutic Delivery, 2(5), 643–672. [DOI:10.4155/tde.11.19]
  • Zhang, Y., Huo, M., Zhou, J., & Xie, S. (2010). PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Computer Methods and Programs in Biomedicine, 99(3), 306–314. [DOI:10.1016/j.cmpb.2010.01.007]
  • Zhou, X. F., Shao, Q. X., Han, X. J., Weng, L. J., & Sang, G. W. (1998). Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of Cyclofem® in Chinese women. Contraception, 57(6), 405–411. [DOI:10.1016/S0010-7824(98)00048-1]
  • -]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People2021-06-11T20:26:25-07:002024-03-30T00:00:00-07:00https://transfemscience.org/articles/sublingual-e2-transfemAn Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People +]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People2021-06-11T20:26:25-07:002025-08-07T00:00:00-07:00https://transfemscience.org/articles/sublingual-e2-transfemAn Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People

    By Sam | First published June 11, 2021 - | Last modified March 30, 2024

    + | Last modified August 7, 2025

    Abstract / TL;DR

    -

    Despite being less well characterised in the medical literature than other formulations, sublingually administered estradiol has been used successfully by several gender clinics around the world. While there may be practical shortcomings associated with the sublingual route, clinical experience and best judgement would suggest it to be effective and affordable when dosed correctly. Sublingual administration of estradiol may be a useful alternative to oral administration for some transfeminine people and can be used for feminising hormone therapy instead.

    +

    Sublingually-administered estradiol is an alternative route of administration to oral estradiol that has been used by a limited number of gender clinics around the world. We do not currently know if sublingual estradiol results in better, worse, or similar feminisation as other routes of administration because there is a paucity of clinical data in this area. There may be practical shortcomings associated with the sublingual route, however clinical experience suggest it to be effective and affordable when dosed correctly. Although much more research is clearly needed to properly characterise this route of administration, sublingual estradiol might have some advantageous properties and may be a useful alternative to oral estradiol for some transfeminine people.

    Introduction

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    Although the most common way to administer medication in the form of pills or tablets is by the oral route, oral estradiol formulations can otherwise be taken sublingually or buccally (Kuhl, 2005). Sublingual administration refers to the placing of the pill or tablet under the tongue to dissolve and be absorbed into the bloodstream. Buccal administration is similar and refers to placing the medication between the cheek and gums, where it also quickly dissolves and is absorbed (Gass et al., 2004; Bartlett & Maarschalk, 2012).

    +

    Although the most common way to administer medication in the form of pills or tablets is by the oral route, oral estradiol formulations can otherwise be taken sublingually or buccally (Kuhl, 2005). Sublingual administration is the administration of an oral pill or tablet by means of placing under the tongue to dissolve and be absorbed into the bloodstream. Buccal administration is similar and refers to placing the medication between the cheek and gums, where it also quickly dissolves and is absorbed (Gass et al., 2004; Bartlett & Maarschalk, 2012).

    Many transfeminine people wonder or ask questions on online forums about the sublingual route of administration for estradiol. Some of the most common queries are “What doses of sublingual estradiol should I take?”, “How often should I take sublingual estradiol?”, “Is sublingual estradiol better than oral estradiol?” and so on.

    -

    Previously, I reviewed the literature in a comparison of oral and transdermal estradiol (Sam, 2020a). Although many transfeminine people experiment with sublingual estradiol and its use appears to be commonplace among those who self-medicate with estrogens, I did not discuss sublingual or buccal routes of administration in this review. In part, the reason for this was because few studies exist concerning the use of sublingual estradiol compared to conventional and more widely used routes. This is likely also the reason that sublingual estradiol is not discussed in many clinical practice guidelines (Aly, 2020a). Moreover, I wanted to focus specifically on oral estradiol. Since the time of publication of that article, however, several new studies of sublingual estradiol in transfeminine people have been published. In light of this new information, and on account of the many questions asked by transfeminine people online, I believe an in-depth look at this route of administration is warranted. So this is intended to be an overview of the published medical literature regarding sublingual estradiol, with a specific focus on its use in transgender care, aiming to answer some of these questions.

    +

    Until very recently, published data about sublingual estradiol in transfeminine people was scarce, with only a very small number of relevant studies having considered it (eg: Jain, Kwan, & Forcier, 2019, Lim et al., 2019). Accordingly, most information about the sublingual route existed only in older studies of cisgender patient populations (Casper & Yen, 1981; Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). In the last few years, there has been a renewed interest in sublingual estradiol within the literature, specifically with an eye towards gender-affirming hormone therapy. Consequently, many high-level publications including recent clinical guidelines and reviews now make reference to the sublingual route (Coleman et al., 2022; Sudhakar et al., 2023; Grock, Reema, & Ahern, 2024).

    -

    It is of note that, although the sublingual and buccal administration are distinct routes of administration, they are very similar to each other in how they are performed and in their pharmacology (Perloff, 1950; Chandrasekhara et al., 2002). As such, although I have ostensibly chosen to make use of the term “sublingual” in this literature review, much of the content here is applicable to buccal administration of estradiol as well.

    +

    It is of note that, although the sublingual and buccal administration are distinct routes of administration, they are very similar to each other in how they are performed and in their pharmacology (Perloff, 1950; Chandrasekhara et al., 2002). As such, although the term “sublingual” has been ostensibly used in this literature review, much of the content here is applicable to buccal administration of estradiol as well.

    Pharmacology of Sublingual Estradiol

    -

    While sublingual estradiol has not been as widely used in clinical practice as oral estradiol and other formulations, a number of studies have examined its pharmacology. These studies include both samples of postmenopausal cisgender women and transfeminine people as well as other patient populations (Casper & Yen, 1981; Serhal & Craft, 1989; Deutsch, Bhakri, & Kubicek, 2015; Cirrincione et al., 2021). Both oral estradiol and oral estradiol valerate tablets can be taken sublingually (Serhal, 1990).

    +

    While sublingual estradiol is not as widely used in clinical practice as oral estradiol and other formulations, a number of studies have examined its pharmacology. These studies include both samples of postmenopausal cisgender women and transfeminine people as well as other patient populations (Casper & Yen, 1981; Serhal & Craft, 1989; Cirrincione et al., 2021; Doll et al., 2022; Kariyawasam et al., 2025). Both oral estradiol and oral estradiol valerate tablets can be taken sublingually (Serhal, 1990).

    -

    After the administration of a dose of oral estradiol, the medication is heavily metabolised and inactivated into estrogen conjugates by the liver (Kuhl, 2005). In turn, these metabolites are gradually converted back into estradiol, which serves to prolong its half life (to approximately 13–20 hours) (Stanczyk, Archer, & Bhavnani, 2013). In contrast to oral estradiol, sublingual estradiol does not pass extensively through the liver and is not significantly deactivated by hepatic metabolism into estrogen metabolites. Instead, sublingually administered estradiol is rapidly absorbed into the bloodstream and directly enters circulation. Consequently, sublingual estradiol has greater bioavailability than oral estradiol, meaning that lower doses are needed to achieve similar AUC estradiol levels (Kuhl, 2005) (Figures 1 and 2). This is an advantage of sublingual estradiol over oral estradiol, as it allows for lower doses to be used and for reduced medication costs.

    +

    After the administration of oral estradiol, the medication is heavily metabolised and inactivated into estrogen conjugates by the liver (Kuhl, 2005). In turn, these metabolites are gradually converted back into estradiol, which serves to prolong its half life (to approximately 13–20 hours) (Stanczyk, Archer, & Bhavnani, 2013). In contrast to oral estradiol, sublingual estradiol does not pass as extensively through the liver. Therefore, it does not undergo deactivation into clinically insignificant estrogen metabolites. Sublingually administered estradiol is absorbed rapidly into the bloodstream where it directly enters circulation. Consequently, it has greater bioavailability than oral estradiol, meaning that lower doses are needed to achieve similar area-under-the-curve (AUC) estradiol levels (Kuhl, 2005) (Figures 1 and 2). This is an advantage of sublingual estradiol over oral estradiol, as it allows for the use of lower doses. This in turn might reduce medication costs.

    @@ -2500,16 +2500,16 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome -
    Figures 1 and 2: Pharmacokinetics in different studies of a single 0.25 to 2 mg dose of micronised estradiol with oral administration (left) and sublingual or buccal administration (right). Sources: Burnier et al. (1981); Casper & Yen (1981); Fiet et al. (1982); Kuhnz, Gansau, & Mahler (1993); Price et al. (1997); Wiegratz et al. (2001); Wren et al. (2003); and Pickar et al. (2015). Dotted black lines represent approximately average integrated estradiol levels in premenopausal women (Verdonk et al., 2019). + Figures 1 and 2: Mean average pharmacokinetics in different studies of a single 0.25 to 2 mg dose of micronised estradiol with oral administration (left) and sublingual or buccal administration (right). Sources: Burnier et al. (1981); Casper & Yen (1981); Fiet et al. (1982); Kuhnz, Gansau, & Mahler (1993); Price et al. (1997); Wiegratz et al. (2001); Wren et al. (2003); and Pickar et al. (2015). Dotted black lines represent approximately average integrated estradiol levels in premenopausal women (Verdonk et al., 2019).
    -

    Because accidental swallowing of some of the estradiol seems probable, the sublingual route is, most likely, actually a combination of sublingual and oral delivery of estradiol (Lobo, 1987; Kuhl, 2005). A preliminary report from an ongoing study of transfeminine people reported that a single 1 mg dose of sublingual estradiol caused an average rise in the level of estradiol up to a maximum of at least 179 pg/mL (657 pmol/L) within one to two hours of administration. In contrast, a peak concentration of just 36 pg/mL (130 pmol/L) was found with the same 1 mg dose administered orally (Doll et al., 2020). Thereafter, estradiol levels decreased rapidly. This response has also been found in other studies of postmenopausal women where a wide range of peak concentrations have been observed (Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). Estradiol levels are found to rapidly rise on the order of ten times that of the peak of oral estradiol, then rapidly decline with an elimination half-life of a few hours (Kuhl, 2005). Sublingual estradiol is somewhat analogous in this respect to intravenously administered estradiol, which also is associated with a rapid increase in estradiol levels and a very short elimination half-life following a dose (Kuhnz, Gansau, & Mahler, 1993). Another route of administration that is similar in this regard is intranasal administration (Devissaguet et al., 1999). Owing to the spikiness and short duration of sublingual estradiol, sublingual estradiol does not achieve as stable of concentrations as other formulations do. As such, this is a marked difference to other formulations of estradiol, such as oral estradiol, that produce much more stable hormone levels that do not fluctuate as much over the course of the day.

    +

    Because accidental swallowing of some of the estradiol seems probable, the sublingual route is, most likely, actually a combination of sublingual and oral delivery of estradiol (Lobo, 1987; Kuhl, 2005). A small pharamcokinetics study of transfeminine people reported that a single 1 mg dose of sublingual estradiol caused an average rise in the level of estradiol up to an average of 144 pg/mL (529 pmol/L) within one to two hours of administration. In contrast, a peak concentration of just 35 pg/mL (128 pmol/L) was found with the same dose of 1 mg administered orally (Doll et al., 2022). Thereafter, estradiol levels decreased rapidly. In another study, it was found that mean estradiol levels measured at any given point were 613 pmol/L (167 pg/mL) on sublingual estradiol (Kariyawasam et al., 2025). In this study, a wide range of doses were used and hence it is not possible to ascertain much about dose-specific peak concentrations. Similar findings have been reported in other studies of postmenopausal women, although a wide range of peak concentrations have been observed (Burnier et al., 1981; Price et al., 1997; Wren et al., 2003). Estradiol levels are found to rapidly rise on the order of about five to ten times that of the peak of oral estradiol, then rapidly decline, with an elimination half-life of only a few hours (Kuhl, 2005). Sublingual estradiol is somewhat analogous in this respect to intravenously administered estradiol, which also shows a rapid increase in estradiol levels and a very short elimination half-life (Kuhnz, Gansau, & Mahler, 1993). Another route of administration that is similar in this regard is intranasal administration (Devissaguet et al., 1999). Owing to the short half-life elimination of sublingual estradiol, it does not achieve as stable concentrations as other formulations do. This is a marked difference to other routes, such as oral estradiol, that produce much more stable hormone levels and that do not fluctuate as much over the course of the day. All these differences by themselves do not necessarily mean that sublingual estradiol is superior or inferior to oral estradiol (Safer, 2022; Sarvaideo, Doll, & Tangpricha, 2022). Nevertheless, they should be kept in mind when considering findings from relevant studies.

    -

    A range of estimates have been reported for the relative bioavailability of sublingual estradiol. One small randomised study of postmenopausal women found approximately 2.5-fold higher area-under-the-curve (AUC) levels of estradiol with sublingual estradiol than with the same doses of oral estradiol (Price et al., 1997). Other studies have reported relative bioavailability estimates for sublingual estradiol of up to five times that of oral estradiol (Pines et al., 1999). A study in marmoset monkeys found that the absolute bioavailability of sublingual estradiol was 10%; approximately twice that of conventional absolute bioavailability estimates of oral estradiol (5%, though with a wide range of 0.1 to 12%) (Kuhnz, Blode, & Zimmermann, 1993). Therefore, with respect to AUC levels of estradiol, the sublingual route appears to have between approximately two and five times higher estradiol levels compared to oral estradiol when given at the same doses. Based on these findings, approximate doses of sublingual estradiol for use in transfeminine hormone therapy can be derived (Table 1). It is of note that, at this time, the comparative potency of sublingual estradiol remains to be properly characterised due to a lack of research.

    +

    A range of estimates have been reported for the relative bioavailability of sublingual estradiol. One small randomised study of postmenopausal women found approximately 2.5-fold higher AUC levels of estradiol with sublingual estradiol than with the same doses of oral estradiol (Price et al., 1997). Other studies have reported relative bioavailability estimates for sublingual estradiol of up to five times that of oral estradiol (Pines et al., 1999). A study in marmoset monkeys found that the absolute bioavailability of sublingual estradiol was 10%; approximately twice that of conventional absolute bioavailability estimates of oral estradiol (5%, though with a wide range of 0.1 to 12%) (Kuhnz, Blode, & Zimmermann, 1993). Therefore, with respect to AUC levels of estradiol, the sublingual route appears to have between approximately two and five times higher estradiol levels compared to oral estradiol when given at the same doses. Based on these findings, approximately equivalent doses of sublingual estradiol can be derived (Table 1). It is notable that due to substantial interindividual variation in the metabolism of different forms of estradiol, these relative doses are unlikely to correspond to one another on a person-by-person basis. Measurement of circulating estradiol concentrations should always be used to guide dose titration.

    Table 1: Approximately comparable doses of estradiol (E2) and estradiol valerate (EV) administered by the oral and sublingual routes in terms of total estradiol exposure (Price et al., 1997; Pines et al., 1999):

    @@ -2555,97 +2555,79 @@ Figure 5. Meta-analysis of estradiol concentration-time data from cisgender wome -

    a Range calculated by dividing oral doses by two and four to reflect differences in absolute bioavailability and rounding to the nearest 0.25 mg. * Bioidentical estradiol has wide interindividual variation in its pharmacology and the effects of doses may vary significantly between individuals. EV has greater molecular weight and therefore contains less medication for the same amount/dose by weight. It should be noted that estimates for the relative bioavailability of EV are extrapolated from formulations with no valeric ester attached (i.e., E2).

    +

    a Range calculated by dividing oral doses by two and four to reflect differences in absolute bioavailability and rounding to the nearest 0.25 mg. * Bioidentical estradiol has wide interindividual variation in its pharmacology and the effects of doses are likely to vary significantly between individuals. EV has greater molecular weight and therefore contains less medication for the same amount/dose by weight. It should be noted that estimates for the relative bioavailability of EV are extrapolated from formulations with no valeric ester attached (i.e., E2).

    + +

    Administration of Multiple Sublingual Doses Per Day

    + +

    In order to compensate for the short half-life of sublingually administered estradiol, multiple doses of estrogens can be administered in smaller quantities per day to maintain hormone levels that are somewhat more consistent (Ahokas, Kaukoranta, & Aito, 1999; Yaish et al., 2023a; Cortez et al., 2024).

    + +

    In one study of premenopausal women with high-dose estrogen therapy, 2 mg of sublingual estradiol was administered three or four times per day (a total of 6–8 mg/day), resulting in significantly more stable hormone levels than would be expected with a single dose per day (Serhal & Craft, 1989). This was replicated in another study where estradiol was administered three to eight times per day (Ahokas et al., 2001). Conversely, a third study investigating low-dose buccal estradiol found little difference between the “steady-state” estradiol concentrations with a once-daily and twice-daily 0.25 mg dose of buccal estradiol over a 12 hour observation period (Wren et al., 2003). These findings may indicate that sublingual and buccal estradiol needs to be taken at least thrice per day in order to achieve concentrations of estradiol that are more stable.

    + +

    It would seem advantageous for transfeminine people using sublingual estradiol that sublingual estradiol is taken in divided doses throughout the day; perhaps ideally at least three or four times per day. For instance, instead of taking a 2 mg dose every 24 hours, it would be better to take four 0.5 mg doses in the space of 24 hours (as evenly spaced as practical). Administering sublingual estradiol multiple times throughout the day might be less convenient, but is likely to provide at least somewhat more balanced estradiol levels. The administration of multiple doses every day could be regarded as optimal for the use of sublingually administered estradiol.

    Sublingually Administered Estradiol and Feminisation

    -

    The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions for its potential use of sublingual estradiol in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.

    +

    The very short half-life of sublingually and buccally administered estradiol relative to other forms raises a few questions relating to its use in feminising hormone therapy. One of the most commonly asked questions on online forums is regarding which gender-affirming hormone therapy regimens might be most “effective” with respect to the feminising effects of estrogens. These include, but are not limited to, outcomes such as breast development and fat distribution.

    -

    In contrast to oral and trandermal estradiol, no data exist describing the extent of feminisation with sublingual estradiol (Sam, 2020a). However, as discussed previously, oral and non-oral estradiol have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogondal girls (Rosenfield et al., 2005; Shah et al., 2014; Klaver et al., 2018; de Blok et al., 2021). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. The fact that several gender clinics have employed sublingual estradiol is also encouraging and suggests that sublingual estradiol is effective for inducing feminization (Deutsch, Bhakri, & Kubicek, 2015; Lim et al., 2019; Cirrincione et al., 2021). Nevertheless, as no studies have been conducted comparing the feminising efficacy of sublingual estradiol with objective measures, it is not possible to say for certain whether or not there is any difference in feminisation outcomes between oral and sublingual estradiol. Hopefully, studies in the future will shed more light on this.

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    In contrast to oral and trandermal estradiol, limited data exist describing the extent of feminisation with the sublingual route (Safer, 2022). A non-randomised study found that self-assessed Tanner stage after 6 months of treatment did not appear to be different in users of sublingual estradiol monotherapy as compared to users of oral estradiol plus 10 mg/day cyproterone acetate (Yaish et al., 2023a; Yaish et al., 2023b). However, since breast development itself was not measured objectively, these particular data are low-quality and prevent definitive conclusions either way about the superiority or inferiority of sublingual estradiol. The same study group reported that although there were similar increases in gynoid fat in the two arms, the oral estradiol group did show an increased amount of android fat as compared to the sublingual group (Yaish et al., 2025). On the other hand, a further complication of this study is the possible confounding by lack of concomitant antiandrogen therapy in the sublingual arm (Ruggles & Cheung, 2024; Yaish et al., 2024). Notably, progestogens like cyproterone acetate have been shown to be associated with weight gain (Lopez et al., 2016). This could explain the difference in android fat accumulation.

    + +

    Oral estradiol and other non-oral forms of estradiol (such as transdermal administration) have not been found to differ in their effects on breast development or other feminising outcomes in transfeminine people or cisgender hypogonadal girls (Rosenfield et al., 2005; Shah et al., 2014; Klaver et al., 2018; de Blok et al., 2021, Tebbens et al., 2022). In consideration of this, differences in efficacy might not be expected for sublingual estradiol either. However, the use of supraphysiological doses of estrogens from the onset of therapy may stunt breast development and reduce final breast size in transfeminine people (Boogers et al., 2025). Because the use of sublingual estradiol results in estradiol concentrations that routinely achieve the supratherapeutic range, it is possible that this could have deleterious effects on breast development.

    + +

    The fact that several gender clinics have employed sublingual estradiol for some time is encouraging (Deutsch, Bhakri, & Kubicek, 2015; Lim et al., 2019; Cirrincione et al., 2021). Nevertheless, as there is very limited data comparing the feminising efficacy of sublingual estradiol with objective measures, no firm conclusions about any differences in feminisation outcomes between sublingual estradiol and other routes of administration can currently be drawn. Hopefully, studies in the future will shed more light on this.

    Testosterone Suppressing Efficacy of Sublingually Administered Estradiol

    Another question that might be raised by the short half-life of sublingual estradiol is how it might compare to more conventional routes of administration in terms of its ability to suppress testosterone and other androgens.

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    Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s, in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (Huggins & Hodges, 1941). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (Stege et al., 1996; Kohli, 2006; Sciarra et al., 2015). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Sublingual estradiol, on the other hand, has never been used as therapy for prostatic cancer and, consequently, no such data exist on the same scale to show the ability of sublingual estradiol in this capacity.

    +

    Estrogens were first characterised for their use as antigonadotrophic antiandrogens in the 1940s in the form of oral synthetic estrogens, namely diethylstilbestrol (DES), to treat men with prostate cancer (Huggins & Hodges, 1941). Estrogens given in the form of oral ethinylestradiol (EE), long-acting estradiol esters, such as polyestradiol phosphate, and transdermal estradiol patches have been studied. Their efficacy for this indication is well established (Stege et al., 1996; Kohli, 2006; Sciarra et al., 2015). As data are more limited for testosterone suppression with estrogens in transfeminine people, these data are valuable for informing transfeminine hormone therapy. Since sublingual estradiol has never been used to treat prostatic cancer, no such data exist to show the ability of sublingual estradiol in this capacity.

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    Recent data from some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (Leinung, Feustel, & Joseph, 2018; Pappas et al., 2020). Additionally, new data from around 900 men enrolled in the ongoing Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, show that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (<50 ng/dL [<1.7 nmol/L]) (Langley et al., 2021). However, because of the markedly different pharmacokinetics of sublingual estradiol, it is plausible that estradiol administered in this way might result in sub-par suppression at doses with similar AUC levels of estradiol. Put another way, sustained estradiol levels may be more efficacious with respect to testosterone suppression than the frequent and short-lived “spikes” in estradiol levels that occur with the sublingual route.

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    Some studies have found that physiologic levels of estradiol (i.e., 100–200 pg/mL [367–734 pmol/L]) or slightly higher from non-sublingual estradiol alone result in rapid and near complete, if not complete, suppression of testosterone levels to the female range in many transfeminine people (Leinung, Feustel, & Joseph, 2018; Pappas et al., 2020; Misakian et al., 2025). Additionally, the Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) study, a multicentre randomised controlled trial in the United Kingdom, showed that sustained median estradiol levels of between 215 to 250 pg/mL (789–918 pmol/L) from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (<50 ng/dL [<1.7 nmol/L]) (Langley et al., 2021). However, because sublingual estradiol differs in its pharmacokinetics to other forms of estradiol, it is plausible that this route of administration might result in sub-par suppression at doses with similar concentrations of estradiol.

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    There is some weak evidence from pharmacological studies of estradiol that support this possibility. One line of evidence is that some studies of both sublingual and intravenous administration have reported rapid but limited suppression of the gonadotropins (follicle-stimulating hormone and luteinising hormone) in women despite sufficiently elevated estradiol levels for several hours (Tsai & Yen, 1971; Burnier et al., 1981; Casper & Yen, 1981; Hoon et al., 1993). These studies are low quality and indirect since testosterone suppression itself was not measured and they were performed in cisgender women. Another problem is that all were single dose studies and their findings may not translate to multiple dosing. It may be the case that full gonadotropin suppression becomes apparent with repeated physiologic doses of sublingual estradiol. Nevertheless, these studies might suggest a limited effect of sublingual estradiol to fully suppress gonadal function in transfeminine people without the use of excessive doses that would lead to greater health risks or the additional use of other antiandrogens.

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    A few studies have reported the extent of testosterone suppression under sublingual estradiol in transfeminine people. In a randomised controlled trial (RCT) comparing once-daily and twice-daily administration of 2 mg sublingual estradiol to 0.1 mcg/day transdermal estradiol with and without spironolactone, both of the sublingual arms were found to result in inferior testosterone suppression at 1-month and 6-month follow-up (Cortez et al., 2023; Cortez et al., 2024). The authors hypothesised that this could be due to the ability of high concentrations of estrone, which were seen with sublingual estradiol, to inhibit cooperative binding of the estrogen receptor. However, this notion is contradicted by studies comparing oral and transdermal administration of estradiol which have reported no difference in the ability of these formulations to suppress testosterone at equivalent doses (SoRelle et al., 2019; Salakphet et al., 2022; Slack et al., 2025). This is in spite of the large amount of estrone also known to be generated from oral estradiol. Another study of transfeminine people found that sublingual estradiol at a dose of 0.5 mg administered four times daily was able to suppress testosterone as well as oral estradiol in combination with low-dose cypoterone acetate (Yaish et al., 2023a; Yaish et al., 2023b). The use of the four times daily dosing regimen in this study may account for the difference in findings between these two studies in the ability to suppress testosterone. Sublingual estradiol has been studied in transfeminine people in combination with and without the low-dose use of the progestin medroxyprogesterone acetate (MPA) (Jain, Kwan, & Forcier, 2019). In this study, high rates of suppressed testosterone levels (ie: <50 ng/dL [<1.7 nmol/L]) were achieved by the transfeminine people who took sublingual estradiol with medroxyprogesterone acetate, showing that sublingual estradiol taken together with progestogens such as cyproterone acetate is viable for achieving effective testosterone suppression.

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    It could be the case that monotherapy with sublingual estradiol may not be as effective at comparable doses to the typically employed doses in studies of prostatic cancer (e.g., two to four 100 μg/24 hours transdermal patches). Transdermal patches, gels and parenteral estradiol esters, such as estradiol valerate, injected intramuscularly or subcutaneously might therefore be more reliable choices for monotherapy regimens. On the other hand, sublingual estradiol has been studied in transfeminine people in combination with and without the low-dose use of the progestin medroxyprogesterone acetate (MPA) (Jain, Kwan, & Forcier, 2019). In this study, at least reasonably high rates of testosterone levels within the female range (<50 ng/dL [<1.7 nmol/L]) were achieved by the transfeminine people who took sublingual estradiol together with medroxyprogesterone acetate, showing that sublingual estradiol taken together with other antiandrogens (e.g., 10 mg/day cyproterone acetate) is very likely to be viable for achieving effective testosterone suppression (Aly, 2019).

    +

    A possibility supported by some evidence from pharmacological studies of estradiol is that sustained estradiol levels may be more efficacious with respect to testosterone suppression than the frequent and short-lived peaks in estradiol concentrations that occur with the sublingual route. In some studies of both sublingual and intravenous administration, limited suppression of the gonadotropins (follicle-stimulating hormone and luteinising hormone) have been reported in women despite sufficiently elevated estradiol levels for several hours (Tsai & Yen, 1971; Burnier et al., 1981; Casper & Yen, 1981; Hoon et al., 1993). These studies are low quality and indirect since testosterone suppression itself was not measured and they were performed in cisgender women. Another problem is that all were single dose studies and their findings may not translate to multiple dosing. Nevertheless, these studies might suggest a mechanism by which sublingual estradiol is unable to fully suppress gonadal function in transfeminine people without the use of excessive doses that would lead to greater health risks or the additional use of other antiandrogens.

    + +

    For the reasons above, transdermal patches, gels and parenteral estradiol esters, such as estradiol valerate, injected intramuscularly or subcutaneously are probably more reliable choices for estradiol monotherapy regimens. If sublingual estradiol is used as a single agent therapy, it would seem reasonable to suggest the use of many divided doses taken throughout the day, as this is probably more likely to be efficacious. Nevertheless, sublingual estradiol appears to be more effective in terms of testosterone suppression when used with concomitant antiandrogens.

    Monitoring of Estradiol Levels with Sublingual Administration

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    A further consideration regarding the rapid changes in estradiol levels that occur with the use of sublingual estradiol is the relevance of monitoring of estradiol levels through bloodwork. Currently, consensus guidelines do not recommend a specific time for monitoring of the blood relative to the time of a last dose (Deutsch, 2016; Cheung et al., 2019; T’Sjoen et al., 2020). This may be in part due to practical reasons, or because there is currently no robust data from randomised controlled trials to guide the specifics of dosing in transgender hormone therapy (Haupt et al., 2020). Nevertheless, because estradiol levels vary so significantly with sublingual estradiol, knowledge of how long after the last dose blood was drawn is important to ensure proper interpretation of laboratory results.

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    A further consideration regarding the rapid changes in estradiol levels that occur with the use of sublingual estradiol is the relevance of monitoring of estradiol levels through bloodwork. Currently, consensus guidelines do not recommend a specific time for monitoring of the blood relative to the time of a last dose (Cheung et al., 2019; T’Sjoen et al., 2020; Coleman et al., 2022). This may be in part due to practical reasons, or because until very recently there were currently no robust data from randomised controlled trials to guide the specifics of dosing in transgender hormone therapy (Haupt et al., 2020). Nevertheless, because estradiol levels vary so significantly with sublingual estradiol, knowledge of how long after the last dose blood was drawn is important to ensure proper interpretation of laboratory results.

    For instance, measuring hormone levels just after a dose of sublingual estradiol has been taken might lead to the misinterpretation that levels of estradiol are excessively high and that one’s dosage should be reduced to achieve a more sensible concentration of estradiol in the blood. In reality, this would be a misunderstanding caused by the pharmacology of sublingual estradiol as the point of measurement would be right around the time when estradiol levels are most likely to be at their highest. These estradiol levels would not be indicative of the average amount of exposure, which is the more accurate measure of overall estrogenicity. Similarly, on the opposite end of the scale, drawing blood just before the administration of a new dose might lead to the belief that estrogen levels are too low and, consequently, lead to the use of excessive doses of estrogens. The latter misinterpretation may be more common among people unfamiliar with the pharmacology of sublingual estradiol as levels of estradiol only remain very high in the first few hours after a dose of sublingual estradiol has been taken before falling rapidly.

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    This oversight may also have implications in studies of sublingual estradiol. For instance, in the previously mentioned respective analysis of the use of sublingual estradiol for gender-affirming hormone therapy, the frequency of administration and time of measurement relative to the last dose were not specified in their results (Jain, Kwan, & Forcier, 2019). Although this data is much needed and is valuable to ongoing research to characterise sublingual estradiol in in transfeminine people, a significant problem is not knowing at what time estradiol levels were measured after the medication was administered. It is difficult to say much about the estradiol levels recorded in this study. Moreover, it is impossible to use this data to help derive equivalent doses of sublingual and oral estradiol.

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    A possible solution to the problem of rapidly changing hormone levels associated with the sublingual route might simply be to measure when estradiol levels are most likely to be closest to their average. In the case of sublingual estradiol, studies generally find this to be approximately four hours after the administration of a dose, although there is likely to be considerable variation between individuals (Kuhl, 2005). Nevertheless, this approach may give the most representative “snapshot” of overall estrogenic exposure and might help to avoid misleading laboratory data in users of sublingual estradiol.

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    Administration of Multiple Sublingual Doses Per Day

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    In order to compensate for the short half-life of sublingually administered estradiol, multiple doses of estrogens can be administered in smaller quantities per day to maintain hormone levels that are somewhat more consistent (Ahokas, Kaukoranta, & Aito, 1999).

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    In one study of premenopausal women with high-dose estrogen therapy, 2 mg of sublingual estradiol was administered three or four times per day (a total of 6–8 mg/day), resulting in significantly more stable hormone levels than would be expected with a single dose per day (Serhal & Craft, 1989). This was replicated in another study where estradiol was administered three to eight times per day (Ahokas et al., 2001). Conversely, a third study investigating low-dose buccal estradiol found little difference between the “steady-state” estradiol concentrations with a once-daily and twice-daily 0.25 mg dose of buccal estradiol over a 12 hour observation period (Wren et al., 2003). These findings may indicate that sublingual and buccal estradiol needs to be taken at least thrice per day in order to achieve concentrations of estradiol that are more stable.

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    For the reasons outlined in the subsections above, it would seem advantageous that transfeminine people using sublingual estradiol employ this approach and take sublingual estradiol in divided doses throughout the day; perhaps ideally at least three or four times per day. For instance, instead of taking a 2 mg dose every 24 hours, it would be better to take four 0.5 mg doses in the space of 24 hours (as evenly spaced as practical). Administering sublingual estradiol multiple times throughout the day might be less convenient, but is likely to provide at least somewhat more balanced estradiol levels and potentially better testosterone suppression. The administration of multiple doses every day could be regarded as optimal for the use of sublingually administered estradiol.

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    Safety and Tolerability

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    Unfortunately, as with the pharmacokinetics of sublingually and buccally estradiol, the published medical literature concerning the safety and tolerability of this route of administration leaves much to be desired. No long term safety data exist for sublingually administered estradiol in the same way that both oral and transdermal estradiol have been rigorously studied in menopausal women (Rovinski et al., 2018; CGHFBC, 2019).

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    Unfortunately, no long term safety data exist for sublingually administered estradiol in the same way that both oral and transdermal estradiol have been rigorously studied in menopausal women (Rovinski et al., 2018; CGHFBC, 2019). The published medical literature concerning the safety and tolerability of this route of administration leaves many questions unanswered.

    Adverse Health Effects of Estrogens

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    With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (Kuhl, 2005; Aly, 2020b). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (Anderson et al., 2004; Mikkola et al., 2005). Although the absolute risk is low in the short-term, these are the most significant health concerns associated with gender-affirming hormone therapy.

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    With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (Kuhl, 2005). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (Anderson et al., 2004; Mikkola et al., 2005). Although the absolute risk is low in the short-term, these are the most significant health concerns associated with gender-affirming hormone therapy.

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    A limited number of studies have assessed the effects of sublingually administered estradiol on the liver (Pines et al., 1999; Lim et al., 2019). These data found similar effects on lipids and cholesterol to other estrogens. One line of evidence that indicates sublingual estradiol has greater hepatic impact than other non-oral forms such as trandermal estradiol is the significantly greater quantities of estrone and estrone sulphate that are generated by this route; a marker of estrogenic exposure in the liver (Burnier et al., 1981; Cirrincione et al., 2021). Intense estrogenic activation in the liver is the mechanism by which non-oral estradiol induces a hypercoagulable state at high doses (Sam, 2020b; Sam, 2020c).

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    A retrospective cohort study in the United States found that the incidence of thromboembolism in transfeminine people with an average dose of 4 mg/day oral estradiol was approximately twice that of cisgender controls not taking hormone therapy after adjusting for confounders (HR 2.0, 95% CI 1.4–2.8 versus reference women) (Getahun et al., 2018). These increases in risks are much lower compared to regimens in transfeminine people in the past that included high doses of synthetic estrogens, however even such increases can significantly increase morbidity and mortality (Morimont, Dogné, & Douxfils, 2020). A 2021 meta-analysis reported an absolute incidence of VTE of 2% in transfeminine people receiving gender-affirming hormone therapy, although with significant between-study heterogeneity (Totaro et al., 2021).

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    While a large body of research does exist concerning the short and long term health effects of estrogens, none of these studies have investigated sublingual or buccal estradiol (Oliver-Williams et al., 2019; Mishra et al., 2021). Given that oral estradiol has greater risks than non-oral estradiol, and that sublingual administration partially but not fully avoids first-pass metabolism, it may be the case that its own risk would be no higher than the risk observed with oral estradiol but no lower than the risk observed with non-oral routes. A retrospective cohort study in the United States found that the incidence of thromboembolism in transfeminine people with an average dose of 4 mg/day oral estradiol was approximately twice that of cisgender controls not taking hormone therapy after adjusting for confounders (HR 2.0, 95% CI 1.4–2.8 versus reference women) (Getahun et al., 2018). These increases in risks are much lower compared to regimens in transfeminine people in the past that included high doses of synthetic estrogens, but it’s important to remember that even such increases can significantly increase morbidity and mortality (Morimont, Dogné, & Douxfils, 2020). It would be advisable to limit doses of sublingual and buccal estradiol so that they are not excessive (i.e., <6 mg/day) in the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy.

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    Some studies have assessed the effects of sublingually administered estradiol on the liver (Pines et al., 1999; Lim et al., 2019). These data found similar effects on lipids and cholesterol to other estrogens. One line of evidence that indicates sublingual estradiol has greater hepatic impact than other non-oral forms such as trandermal estradiol is the significantly greater quantities of estrone and estrone sulphate that are generated by this route; a marker of estrogenic exposure in the liver (Burnier et al., 1981; Cirrincione et al., 2021). Intense estrogenic activation in the liver is the mechanism by which non-oral estradiol induces a hypercoagulable state at high doses (Kuhl, 2005). While a large body of research does exist concerning the short and long term health effects of estrogens, none of these studies have investigated sublingual or buccal estradiol (Oliver-Williams et al., 2019; Mishra et al., 2021). Given that oral estradiol has greater risks than non-oral estradiol, and that sublingual administration partially but not fully avoids first-pass metabolism, it may be the case that its own risk would be somewhere between the risk observed with oral estradiol and the risk observed with other conventional non-oral routes (such as transdermal estradiol). However, an ongoing prospective study reported that use of sublingual estradiol alone resulted in less favourable outcomes on some markers of coagulation in the liver as compared to oral estradiol and cyproterone acetate (Bar et al., 2024). These data are indirect, however could suggest that contrary to theoretical expectations, sublingual estradiol might be closer or even less favourable than the risk profile of oral estradiol.

    + +

    Other adverse effects of estradiol include breast cancer and gallbladder disease. These risks are believed to be dose-dependent (Cummings et al., 1999; Liu et al., 2008). However, as with cardiovascular and thromboembolic complications, no data exist to describe the long-term risk in these other areas with sublingual formulations. In the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy, it would be advisable to limit doses of sublingual and buccal estradiol so that they are not excessive (i.e., <6 mg/day) (Jalal & Baldwin, 2023).

    Non-compliance

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    A practical obstacle to the use of sublingual estradiol in transfeminine people is that it may be highly inconvenient to have to administer doses thrice, four times or perhaps even more often throughout the duration of a single day. It has been found in observational studies that, in general, the number of prescribed medications and doses per day are positively associated with patient non-compliance and the number of missed doses (Jin et al., 2008; Toh et al., 2014). These findings are especially of relevance to transfeminine people as, in most cases, we require decades of hormone therapy. While missing one dose from time to time may be of little consequence, missing doses repeatedly could be more problematic.

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    A practical obstacle to the use of sublingual estradiol in transfeminine people is that it may be highly inconvenient to have to administer doses thrice, four times or perhaps even more often throughout the duration of a single day. It has been found in observational studies that, in general, the number of prescribed medications and doses per day are positively associated with patient non-compliance and the number of missed doses (Jin et al., 2008; Toh et al., 2014). These findings are especially of relevance to transfeminine people as, in most cases, we require decades of hormone therapy. While missing one dose from time to time may be of little consequence, missing doses repeatedly could be more problematic. Despite this, sublingual estradiol has been used in studies of transfeminine people where it has been administered up to four times daily (Yaish et al., 2023a).

    In contrast to sublingual estradiol, the half-life of oral estradiol and transdermal gel is long enough to enable once-daily administration (Wiegratz et al., 2001; Potts & Lobo, 2005). In the case of transdermal patches and parenteral estradiol, these forms only have to be replenished every few days or after even longer intervals of time (Thurman et al., 2013; Wisner et al., 2015). Therefore, when considering the use of sublingual estradiol versus other forms, whether or not it would be practical or convenient to consistently take medication several times a day should probably also be an important consideration for transfeminine people. If not, then another formulation may be preferable for the person in question. This may be especially true for long term use.

    Summary and Conclusions

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    There is much less research investigating sublingual and buccal estradiol than other forms of estrogen. These forms, namely oral and transdermal estrogens, are used in the alleviation of the menopause and for other indications that have historically been more widely used. As a result, they have received much more attention and characterisation than sublingual estradiol has for transfeminine hormone therapy. However, several recent studies have added to our knowledge of sublingual estradiol. Clinical practice guidelines for transgender care that have historically not discussed the use of sublingual estradiol may be adjusted accordingly if more information becomes available.

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    Sublingual estradiol is different in its pharmacology to other routes. The main difference is that it is associated with a rapid rise and fall in estradiol levels. It has between two and four times the bioavailability of oral estradiol and hence provides the same total estradiol exposure at doses that are two to four times lower. This could be a particular advantage because sublingual estradiol, therefore, is cheaper than oral estradiol.

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    Sublingual estradiol is different in its pharmacology to other formulations. The main difference is that it is associated with a rapid rise and fall in estradiol levels. It has between two and four times the bioavailability of oral estradiol and hence provides the same total estradiol exposure at doses that are two to four times lower. This is a particular advantage because sublingual estradiol, therefore, is cheaper than oral estradiol, and the higher estradiol levels at the same dose may be helpful for testosterone suppression.

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    There is much less research investigating sublingual estradiol than other forms of estrogen. These forms, such as oral and transdermal estrogens, are widely used in the alleviation of the menopause and for other indications. Consequently, they have received much more attention and characterisation than sublingual estradiol has for transfeminine hormone therapy. However, studies are beginning to add our knowledge of sublingual estradiol. Clinical practice guidelines for transgender care, which historically did not make reference to the use of sublingual estradiol, have now begun to discuss it.

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    While no evidence exists to show or suggest that sublingual estradiol results in better or inferior feminisation to that experienced with other routes of administration, it is plausible that sublingual estradiol may to some degree result in less testosterone suppression at the same total estradiol exposure. Sublingual estradiol has, nonetheless, been shown to be effective with respect to testosterone suppression when paired with other antiandrogens. Care should be taken with sublingual estradiol when monitoring estradiol levels to ensure correct interpretation. In order to help minimise these potential problems, sublingual estradiol can be taken in multiple doses divided throughout the day.

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    The evidence is inconclusive regarding whether sublingual estradiol results in better, worse, or the same feminisation when compared with other routes of administration. However, it is plausible that the supra-physiologic levels of estradiol that frequently occur with sublingual estradiol could be detrimental to breast development. It also seems that sublingual estradiol could result in lesser testosterone suppression when used as a single agent therapy as compared to other routes. Sublingual estradiol has, nonetheless, been shown to be effective with respect to testosterone suppression when paired with other antiandrogens. Care should be taken with sublingual estradiol when monitoring estradiol levels to ensure correct interpretation. In order to help minimise these potential problems, sublingual estradiol can be taken in multiple doses divided throughout the day.

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    The health risks of sublingual estradiol have not been quantified in large observational or randomised studies. Therefore, although the partial bypassing of the first pass through the liver is reassuring in this respect, its cardiovascular risk profile is unknown. Sublingual estradiol may be inconvenient and other formulations can be used instead if preferred, particularly for more long-term therapy.

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    The health risks of sublingual estradiol have not been quantified in large observational or randomised studies. Therefore, although the first pass effect in the liver is partially avoided, the cardiovascular risks associated with long-term sublingual estradiol remain unknown. Sublingual estradiol may also be inconvenient and other formulations can be used instead if preferred, particularly for more long-term therapy.

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    Taken together, although much more research is clearly needed to properly characterise the route, sublingual estradiol may have a number of advantageous properties and may be a useful alternative to oral estradiol in transfeminine hormone therapy.

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    Updates

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    Update 1: New Sublingual Estradiol Studies (Added By Aly)

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    Since this article was first published, the following new relevant studies and papers on sublingual estradiol in transfeminine people have been published:

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    • Doll, E., Gunsolus, I., Thorgerson, A., Tangpricha, V., Lamberton, N., & Sarvaideo, J. L. (2022). Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women. Endocrine Practice, 28(3), 237–242. [DOI:10.1016/j.eprac.2021.11.081] -
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      • Safer, J. D. (2022). Are the Pharmacokinetics of Sublingual Estradiol Superior or Inferior to Those of Oral Estradiol? Endocrine Practice, 28(3), 351–352. [DOI:10.1016/j.eprac.2021.12.018]
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      • Sarvaideo, J., Doll, E., & Tangpricha, V. (2022). More Studies Are Needed to Establish the Safety and Efficacy of Sublingual Estradiol in Transgender Women. Endocrine Practice, 28(3), 353–354. [DOI:10.1016/j.eprac.2022.01.004]
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    • Cortez, S., Moog, D., Lewis, C., Williams, K., Herrick, C., Fields, M., Gray, T., Guo, Z., Nicol, G., & Baranski, T. (2023). Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial. JMIR Research Protocols, 12, e53092. [DOI:10.2196/53092]
    • -
    • Jalal, E., & Baldwin, C. (2023). Supratherapeutic Estrogen Levels in Transgender Women Likely From Sublingual Estradiol. Journal of the Endocrine Society, 7(Suppl 1) [ENDO 2023 Abstracts Annual Meeting of the Endocrine Society], A1095–A1096 (abstract no. SAT391/bvad114.2062). [DOI:10.1210/jendso/bvad114.2062] [PDF]
    • -
    • Yaish, I., Gindis, G., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., & Tordjman, K. (2023). Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgender Health, 8(6), 485–493. [DOI:10.1089/trgh.2023.0022] -
        -
      • Gindis, G., Yaish, I., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., & Tordjman, K. (May 2023). Sublingual estradiol only, offers no apparent advantage over combined oral estradiol and cyproterone acetate, for Gender Affirming Hormone Therapy (GAHT) of treatment-naive transwomen: Results of a prospective pilot study. Endocrine Abstracts, 90 [25th European Congress of Endocrinology 2023, 13–16 May 2023, Istanbul, Turkey], 274–274 (abstract no. P182). [DOI:10.1530/endoabs.90.p182] [PDF]
      • -
      • Yaish, I., Gindis, G., Greenman, Y., Shefer, G., Buch, A., Arbiv, M., Moshe, Y., Sofer, Y., & Tordjman, K. M. (October 2023). Sublingual Estradiol Only, Compared To Combined Oral Estradiol And Cyproterone Acetate,Offers No Apparent Advantage For Gender Affirming Hormone Therapy (GHAT), In Treatment Naïve Transwomen: Results Of A Prospective Pilot Study. Journal of the Endocrine Society, 7(Suppl 1) [ENDO 2023 Abstracts Annual Meeting of the Endocrine Society], A1104–A1105 (abstract no. SAT409/bvad114.2080). [DOI:10.1210/jendso/bvad114.2080] [PDF]
      • -
      -
    • -
    • Kariyawasam, N. M., Ahmad, T., Sarma, S., & Fung, R. (2024). Comparison of Estrone/Estradiol Ratio and Levels in Transfeminine Individuals on Different Routes of Estradiol. Transgender Health, online ahead of print. [DOI:10.1089/trgh.2023.0138]
    • -
    +

    Taken together, although much more research is clearly needed to properly characterise sublingual estradiol in transfeminine hormone therapy, it might have some advantageous properties and may be a useful alternative to oral estradiol.

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    {"first_name"=>"Sam", "last_name"=>"S.", "author-link"=>"/about/#sam", "articles-link"=>"/articles-by-author/sam/"}
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    {"first_name"=>"Sam", "last_name"=>"S.", "author-link"=>"/about/#sam", "articles-link"=>"/articles-by-author/sam/"}
    Clinical Guidelines with Information on Transfeminine Hormone Therapy2020-11-20T10:00:00-08:002024-11-17T00:00:00-08:00https://transfemscience.org/articles/transfem-hormone-guidelinesClinical Guidelines with Information on Transfeminine Hormone Therapy