By Sam S. | First published June 11, 2021
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.
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 S., 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 W., 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.
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 to 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). 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: 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; 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 within one to two hours of administration. In contrast, a peak concentration of just 36 pg/mL 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). 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: 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 Dose||Moderate Dose||High Dose||Very-High Dose|
|Oral E2||2 mg/day||4 mg/day||8 mg/day||10 mg/day|
|Sublingual E2a||0.5–1 mg/day||1–2 mg/day||2–4 mg/day||2.5–5 mg/day|
|Oral EV||3 mg/day||6 mg/day||10 mg/day||12 mg/day|
|Sublingual EVa||0.75–1.5 mg/day||1.5–3 mg/day||2.5–5 mg/day||3–6 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 (ie: E2).
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 S., 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.
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, 2005; 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 studies from some studies have found that physiologic levels of estradiol (ie: 100 to 200 pg/mL) 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 from transdermal patches were similarly effective (~95%) to GnRH analogues in reducing testosterone levels to the castrate range (<50 ng/dL) (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 (eg: 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) were achieved by the transfeminine people who took sublingual estradiol together with medroxyprogesterone acetate, showing that sublingual estradiol taken together with other antiandrogens (eg: 10 mg/day cyproterone acetate) is very likely to be viable for achieving effective testosterone suppression (Aly W., 2019).
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.
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 to 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.
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).
With sufficient exposure, owing to their effects in the liver, estrogens are associated with an increased risk of blood clots (Kuhl, 2005; Aly W., 2020b). Additionally, under certain circumstances, estrogens can be associated with other cardiovascular complications (WHI, 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 S., 2020b; Sam S., 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 (ie: <6 mg/day) in the interest of harm reduction and the balancing of the risks and benefits of gender-affirming hormone therapy.
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.
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.