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Analysis of Sublingual Estradiol and Medroxyprogesterone Acetate (MPA) in Transfeminine People Based on Jain et al. (2019) and Deutsch et al. (2015)

By Aly W. | First published June 15, 2019 | Last modified December 18, 2021

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

Introduction

A new study on sublingual estradiol with and without medroxyprogesterone acetate (MPA) in transfeminine people was published by Jain and colleagues in April 2019:

  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results from a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, jc.2018-02253. [DOI:10.1210/jc.2018-02253]

This study is notable in that it is the first to systematically evaluate MPA in transfeminine people. It is also notable in that it is one of the first studies to assess suppression of testosterone levels with sublingual estradiol in transfeminine people. This is is important, as not only can it provide us with an idea of testosterone suppression with sublingual estradiol, it can provide this information across a wide dose range of sublingual estradiol.

Study Summary

Methods

The study compared two medications regimens in transfeminine people in terms of estradiol, testosterone, and prolactin levels, various other biochemical parameters, and a number of self-reported desired and adverse effects:

  1. Sublingual estradiol 2–12 mg/day spironolactone 100–200 mg/day.
  2. Sublingual estradiol 2–12 mg/day, spironolactone 100–200 mg/day, and sublingual MPA 5–10 mg/day or MPA by intramuscular injection 150 mg/3 months.

Estradiol levels were maintained within a range of 100 to 350 pg/mL, with a dosage reduction of sublingual estradiol if estradiol levels were consistently above 350 pg/mL. Unfortunately, details on when and how estradiol levels were tested were not provided. [Edit/Update: Sublingual estradiol was taken once or twice a day “depending on the patient”; personal communication with the contact author.] Addition of MPA was a matter of patient preference.

In terms of design and subjects, the study was a retrospective analysis of 290 follow-up visits from a total of 92 transfeminine people. Of these follow-up visits, 102 were with MPA (from 39 total patients) and 188 were without MPA (from 53 total patients).

Results

As expected, the study found no difference in estradiol levels with versus without MPA (211 pg/mL vs. 210 pg/mL). Conversely, a significant decrease in testosterone levels was observed with inclusion of MPA relative to without MPA (79 ng/dL vs. 215 ng/dL; 63% decrease). There were no differences in prolactin levels with versus without MPA. The study also found minimal differences in other biochemical laboratory parameters with versus without MPA.

Of the transfeminine people who received MPA, 26 of 39 of them (67%) reported improved breast development with MPA, 11 of 39 of them (28%) reported decreased facial hair with MPA, and 5 of 39 of them (13%) reported mood swings with MPA. One patient discontinued MPA due to mood swings. There were no incidences of a variety of health conditions after addition of MPA.

Discussion

The authors concluded that they found minimal side effects, unchanged estradiol levels, decreased testosterone levels, and minimal other biochemical changes in association with MPA.

The authors stressed the need for prospective studies to more thoroughly evaluate MPA in transfeminine people however. They additionally stated the following:

The transgender population would benefit from more in-depth investigations of MPA. […] Moreover, comparative studies of MPA and natural progesterone (Prometrium) are needed. Current clinical recommendations are largely based on patient preference and/or anecdotal evidence, as the relative risks and benefits of MPA and natural progesterone in GAH therapy are unknown. Thus, the transgender population would be well served by future studies such as these described. […] Future studies should be conducted to confirm our findings, systematically assess the safety of MPA, and further investigate the effects of MPA in transgender persons.

Commentary

As mentioned above, this is, to my knowledge, the first study to assess suppression of testosterone levels with sublingual estradiol. And, not only that, it assessed this across a wide range of sublingual estradiol dosages (2–12 mg/day).

Unfortunately however, the researchers did not include mean values for estradiol and testosterone levels with the different dosages of sublingual estradiol in the relevant data table in the paper. Moreover, in the relevant graph, due to a lack of data, they opted to correlate testosterone levels with estradiol levels instead of with sublingual estradiol dosage (see graphs below). As such, the influence of different dosages of sublingual estradiol cannot be readily determined. I have emailed the lead researcher asking about the mean estradiol/testosterone levels for each estradiol dosage and am waiting to hear back. It may also be possible to manually extract this information from the graphs included in the paper (similarly to what I did previously—Aly W., 2019), albeit with a bit of work. (I will update this article if/when I end up doing this. Edit/Update: I ended up doing so. See the graphs/tables below.)

In any case, considering the dosage range of sublingual estradiol used in the study (2–12 mg/day) and the reasonably expansive allowed target range of estradiol levels (100–350 pg/mL), the testosterone levels in transfeminine people without MPA were surprisingly high (215 ng/dL). Although more analysis to see exactly what is going on is required, this is not really encouraging in terms of suppression of testosterone levels with sublingual estradiol monotherapy. Edit/Update: More analysis done. See below.

The study also assessed the value of 5 to 10 mg/day sublingual MPA (as well as 150 mg/3 months intramuscular MPA) in transfeminine people. As MPA has 100% oral bioavailability, we’d expect 5 to 10 mg/day oral MPA and 5 to 10 mg/day sublingual MPA to be essentially equivalent. The study found a considerable decrease in testosterone levels (-63%; 215 ng/dL to 79 ng/dL) with the addition of relatively low doses of MPA to sublingual estradiol plus spironolactone therapy.

The researchers stated that 67% of the transfeminine people who took MPA self-reported that their breast development was improved. However, considering the anecdotal and subjective nature of these reports as opposed to objective measurements, we should take this finding with a grain of salt. As has been discussed elsewhere, there is no evidence at this time that progestogens have lasting beneficial effects on breast development in terms of size and shape, and there is decent reasoning to assume that they may in fact not have any such effects (Aly W., 2019; Wiki).

The researchers also stated that 13% of the transfeminine people (five in total) who took MPA self-reported mood swings. However, these reports are, likewise, anecdotal in nature rather than based on more systematic measurements, and we should be cautious in interpreting them as well. Rigorous and high-quality clinical studies suggest that MPA has little or no risk of adverse mood changes in cisgender women (Wiki).

Graphs

Recreated Graphs

Two graphs from the paper have been recreated during the data extraction process. Unfortunately, they are not perfect—it was not possible to extract the points perfectly because many of them overlapped. In any case, the extracted data is fairly close to the original data. It’s mostly just the estradiol + MPA trend line (and by extension points) for the first graph below that is slightly off.

Figure 1: Sublingual estradiol and spironolactone with and without medroxyprogesterone acetate.
Figure 2: Relationship between estradiol and testosterone levels during treatment with sublingual estradiol and spironolactone with and without medroxyprogesterone acetate.

New Graphs

Here are two new graphs created using the extracted data:

Figure 3: Estradiol levels with different doses of sublingual estradiol. Time after administration not specified. Probably random and hence these estradiol levels might be indicative of “average” levels. Edit/Update: Sublingual estradiol was administered once or twice a day “depending on the patient” (personal communication with study author).
Figure 4: Testosterone levels with different levels of estradiol during therapy with different doses of sublingual estradiol, as well as spironolactone and medroxyprogesterone acetate. The points represent the averages of bins/intervals of 50 pg/mL estradiol. Higher estradiol levels were not included due to insufficient data points.

Data Tables

Estradiol and Testosterone Levels with Sublingual Estradiol

From the extracted data, the following rough and approximate table of testosterone suppression with sublingual estradiol (in combination with spironolactone) can be constructed:

Table 1: Estradiol and testosterone levels with different doses of sublingual estradiol in transfeminine people (Jain et al., 2019):

Sublingual estradiol dosageEstradiol levelsaTestosterone levels
2 mg/day~50 pg/mL~235 ng/dL
4 mg/day~100 pg/mL~200 ng/dL
6 mg/day~150 pg/mL~115 ng/dL
8 mg/day~250 pg/mL~50 ng/dL
10 mg/day~300 pg/mL≤50 ng/dL
12 mg/day~500 pg/mL≤50 ng/dL

a Time of testing after administration and frequency of administration not specified. [Edit/Update: Sublingual estradiol was taken once or twice a day “depending on the patient” (personal communication with study author).] The timings of the blood draws after sublingual estradiol administration were presumably random and hence the estradiol levels might be indicative of “average” levels.

More Commentary

The estradiol levels and testosterone suppression with sublingual estradiol that were observed in this study are much lower than the present author would have expected. It is unclear if this study is just an outlier or if the data are indeed accurate. One point that comes to mind however is that the authors did not describe the dosing regimen for sublingual estradiol, and it’s possible that the patients were only taking sublingual estradiol once per day. [Edit/Update: Sublingual estradiol was taken once or twice a day “depending on the patient” (personal communication with study author).] This could result in a lack of sustained estradiol levels and consequently might account for suboptimal testosterone suppression.

Update

As it turns out, Jain et al. (2019) is actually not the first study of sublingual estradiol in transfeminine people. The first was by Maddie Deutsch and colleagues in 2015:

  • Deutsch, M. B., Bhakri, V., & Kubicek, K. (2015). Effects of cross-sex hormone treatment on transgender women and men. Obstetrics and Gynecology, 125(3), 605–610. [DOI:10.1097/AOG.0000000000000692]

They specifically assessed sublingual micronized estradiol 2 mg twice daily (4 mg/day total) plus 100 to 200 mg/day spironolactone in 14 transfeminine people. Here are the results of their study:

Table 2: Median hormone levels with 2 mg 2x/day sublingual estradiol per Deutsch et al. (2015):

HormoneBaseline6 monthsFraction with physiological levels
Estradiol29 pg/mL258 pg/mL16/16 (100%)
Total testosterone405 ng/dL42 ng/dL10/15 (67%)
Free testosterone11.4 ng/dL0.8 ng/dL14/15 (93%)

The above data also included 2 transfeminine people who were not on sublingual estradiol—one was on a single 100 μg/day transdermal estradiol patch and another was on 20 mg estradiol valerate by intramuscular injection once every 2 weeks. Since the above values are median values and percentages however, the influence of the two patients not on sublingual estradiol should not be overly significant.

As can be seen, testosterone suppression was much better in this study than in Jain, Kwan, & Forcier (2019). The reason for this is unclear but may have been related to the fact that sublingual estradiol was consistently taken twice a day in this study whereas it was taken once or twice per day depending on the patient in Jain, Kwan, & Forcier (2019). More frequent administration of sublingual estradiol and hence more sustained estradiol levels may provide better testosterone suppression.