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Notes on Sublingual Estradiol Valerate

By Aly W. | First published January 5, 2019 | Last modified November 27, 2020

This page is for notes on sublingual administration of oral estradiol valerate tablets.

Serhal and Craft studied the use of oral estradiol valerate tablets (Progynova) administered sublingually 3 to 4 times per day in premenopausal women. They reported their findings in the following two publications:

Their results in terms of hormone levels were as follows (top is controls, bottom is treated women):

These findings indicate that sublingual estradiol valerate is well-absorbed and achieves high estradiol levels similarly to sublingual estradiol.

Here is a section on Wikipedia about the study and about sublingual estradiol valerate in general. See also here and here for more discussion on sublingual estradiol valerate.

The following literature excerpt is also notable (Lim et al., 2019):

Gender Affirmative Care of Transgender People: A Single Center’s Experience in Korea (Lim et al., 2019)

“When we prescribed estradiol, we preferred sublingual estradiol valerate instead of the oral form for feminizing HT since prior researchers have reported the effectiveness of sublingual administration in maintaining high blood estradiol concentration and low E1/E2 ratio [13].”

Edit/Update

All oral estradiol tablets are micronized, and the oral estradiol valerate tablets used in the study by Serhal and Craft were micronized as well. Micronization is thought to be important or possibly essential for proper absorption with the sublingual route. The following excerpt touches on this issue:

The drugs that are administered sublingually generally have low solubility. Therefore, to enhance dissolution, it is crucial to reduce and control the particle size of the [active pharmaceutical ingredient (API)]. This attribute is important in the case of all drugs with low solubility. However, a tighter control on particle size of API is desirable in sublingual drug products to maintain the reproducible quality and performance of the drug product in view of the limited window of dissolution and absorption time. (Sayeed & Ashraf, 2014)

It seems that Progynova tablets, and possibly all oral estradiol valerate tablets, are micronized similarly to oral estradiol tablets. This is per the following sources and excerpts, as well as Progynova medication packaging and other sources:

Oestradiol valerate and oestradiol in a micronized form are the most widely used oestrogen per os for steroid substitution therapy. Our regimen, as of most other groups […] is oestradiol valerate (Progynova; Schering, Berlin, Germany) given in various concentrations throughout the cycle […]. According to Norfolk’s protocol, 2 mg of micronized oestradiol valerate are given on cycle days 1–5. […] In tablet form, micronized oestradiol valerate is also efficiently absorbed […] (Devroey & Pados, 1998)

One possible caveat however is that oral estradiol and oral estradiol valerate tablets were designed for oral use and not specifically for use via the sublingual route. Although many such tablets do clearly work quite well via the sublingual route, these tablets vary in whether they are sugar-coated or film-coated and in their composition/excipients. Such differences in properties could possibly influence sublingual use in an unfavorable way (Sayeed & Ashraf, 2014):

The conditions prevailing in the oral cavity for disintegration and dissolution of sublingual tablets are markedly different from the tablets that are orally ingested. […] Other specialized [oral] tablets, such as modified-release or enteric-coated tablets, may also partly release the drug in the stomach. In contrast, sublingual tablets are designed to completely disintegrate and dissolve in the oral cavity under the tongue.

The main concern is that some tablets might have impeded dissolution when taken sublingually. One study of oral estradiol tablets used sublingually reported that they dissolved within 1 or 2 minutes (Burnier, 1981). Anecdotally, this has been my experience with generic sugar-coated oral estradiol tablets (Photo); the tablets dissolve when held under the tongue within a few minutes at most. But Redditor u/swflcpl has been using oral estradiol valerate tablets (specifically Progynova brand—notably the same brand name used in the study) via the buccal route for several months and has reported that the tablets take about an hour to fully dissolve (Reddit; see also Reddit). This doesn’t seem to adversely affect the bioavailability of her estradiol valerate, as her estradiol and estrone levels are high and her testosterone levels are fully suppressed (with sublingual estradiol valerate alone). But clearly the tablets should not be taking an hour to dissolve. So this is something that should perhaps be kept in mind when using oral estradiol valerate tablets (and possibly also oral estradiol tablets) via the sublingual route—different brands may vary in sublingual/buccal suitability/dissolution rate.