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Sublingual Estradiol and Oral Medroxyprogesterone Acetate (MPA) in Transfeminine People Based on Jain et al. (2019)

By Aly W. | First published June 15, 2019 | Last modified November 21, 2020

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 transgender women was published by Jain and colleagues in late 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 transgender women. It is also notable in that, to my knowledge, it is the first study to assess suppression of testosterone levels with sublingual estradiol in transgender women. [Edit/Update: This was actually incorrect; see below.] 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 dosage range of sublingual estradiol (see below).

Study Summary

Methods

The study compared two groups on estradiol, testosterone, and prolactin levels, various other biochemical parameters, and a number of self-reported desired and adverse effects:

  1. Transgender women treated with 2–12 mg/day sublingual estradiol and 100–200 mg/day oral spironolactone.
  2. Transgender women treated with 2–12 mg/day sublingual estradiol, 100–200 mg/day oral spironolactone, and 5–10 mg/day sublingual MPA or 150 mg/3 months intramuscular MPA.

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 transgender women. 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 transgender women 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 blood clots, cardiovascular disease, prolactinoma, galactorrhea, cholelithiasis, breast cancer, or diabetes 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 transgender women 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 to 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 to 12 mg/day) and the reasonably expansive allowed target range of estradiol levels (100 to 350 pg/mL), the testosterone levels in transgender women 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 transgender women. 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 inclusion of relatively low dosages of MPA with sublingual estradiol therapy.

The researchers stated that 67% of the transgender women who took MPA self-reported that their breast development was improved. However, considering the anecdotal/subjective nature of these reports as opposed to objective measurements, we should take this finding with a grain of salt. As I’ve discussed elsewhere, there is no evidence that progestogens have true beneficial effects on breast development in terms of size and shape, and there is good reason to assume that they do not have any such effects (Aly W., 2019; Wiki).

The researchers also stated that 13% of the transgender women (five in total) who took MPA self-reported mood swings. However, these reports are, likewise, anecdotal/subjective in nature rather than objective. Hence, we should be cautious about them as well. Much more rigorous and high-quality clinical studies support the notion that MPA has no risk of adverse mood changes in cisgender women (Wiki). This likely applies to transgender women as well.

Original Graphs

“Figure 1. Serum estradiol versus dose of estradiol in patients adhering to regimens of estradiol (E) and spironolactone (spiro), with or without MPA. Legend: E + spiro + MPA (red), E + spiro only (blue).”
“Figure 2. Total serum testosterone versus serum estradiol in patients adhering to regimens of estradiol (E) and spironolactone (spiro), with or without MPA. Legend: E + spiro + MPA (red), E + spiro only (blue).”

Recreated Graphs

I’ve recreated the two graphs from the paper so that I could extract the data from them. Unfortunately, they’re not perfect; it was impossible to get the points perfectly right because many of them overlapped. But the data is fairly close in any case. It’s mostly just the estradiol + MPA trend line (and by extension points) for the first graph below that’s 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 fully new graphs I created using the extracted data:

Estradiol levels with different dosages 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”.

Testosterone levels with different levels of estradiol during therapy with different dosages 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.

New Table

From the data in the graphs, we can make the following rough/approximate table for sublingual estradiol monotherapy:

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).] 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

I have to say, the estradiol levels and testosterone suppression with sublingual estradiol that were observed in this study are much lower than I would have expected. I don’t know if it’s just something to do with the study or if the data is indeed accurate. One thing that does come to mind however is that the authors did not describe the dosing regimen, and it’s possible that the patients were only taking their sublingual estradiol once a day. [Edit/Update: Sublingual estradiol was taken once or twice a day “depending on the patient.”] This could hypothetically result in a lack of sustained estradiol levels and consequently sub-par testosterone suppression.

Update

I just wanted to follow up and clarify that this is actually not the first study of sublingual estradiol in transgender women! An earlier study by Madeline Deutsch and colleagues here assessed sublingual micronized estradiol 2 mg twice daily (4 mg/day total) plus 100 to 200 mg/day spironolactone in 14 transgender women. Here are the results (median values):

 Baseline6 months# with physiological levels at 6 months
Estradiol levels29 pg/mL258 pg/mL16/16 (100%)
Total testosterone levels405 ng/dL42 ng/dL10/15 (67%)
Free testosterone levels11.4 ng/dL0.8 ng/dL14/15 (93%)

Note however that the above also included 2 transgender women 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, their influence should not be that significant though.

As should be readily apparent, testosterone suppression was much better in this study.