Dose-Ranging Data on Estradiol Patches and Testosterone Suppression in Cisgender Men Based on de Ronde et al. (2009)

By Aly | First published April 3, 2020 | Last modified March 1, 2023

Introduction

Estrogens dose-dependently suppress testosterone levels in gonadally intact cisgender men and transfeminine people (Wiki; Graphs; Aly, 2018; Aly, 2019; Aly, 2019). We have data showing testosterone suppression for oral estradiol, sublingual estradiol, transdermal estradiol, and injectable estradiol esters. Much of this data is for relatively high estradiol levels however (e.g. >200 pg/mL [>734 pmol/L]). The data we have on testosterone suppression with lower estradiol levels, particularly with transdermal estradiol, are not as substantial.

Recently, I came across the following dose-ranging studies of transdermal estradiol patches on levels of testosterone and other hormones in cisgender men and transfeminine people:

• de Ronde, W., Ten Kulve, J., Woerdeman, J., Kaufman, J. M., & De Jong, F. H. (2009). Effects of oestradiol on gonadotrophin levels in normal and castrate men. Clinical Endocrinology, 71(6), 874–879. [DOI:10.1111/j.1365-2265.2009.03573.x]

• Raven, G., de Jong, F. H., Kaufman, J. M., & de Ronde, W. (2006). In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. The Journal of Clinical Endocrinology & Metabolism, 91(9), 3324–3328. [DOI:10.1210/jc.2006-0462]

The purpose of the studies was to help delineate the role of estradiol on control of the hypothalamic–pituitary–gonadal (HPG) axis in people with testes. These papers happen to have some excellent data on testosterone suppression with different low doses and levels of transdermal estradiol patches that are relevant to transfeminine people, so I thought I would share and discuss their findings.

The results of the two studies in the gonadally intact cisgender men were very similar and seem to have been largely the same individuals and set of data. As such, I’ll only describe the results presented in the more recent paper (de Ronde et al., 2009). In addition, I’ll only describe the paper in relation to the findings in gonadally intact cisgender men, since the post-gonadectomy transfeminine people in the study had low baseline testosterone levels and hence provided no direct information on testosterone suppression (only on estradiol levels) with transdermal estradiol patches.

Methodology

The study employed an estrogen synthesis inhibitor (specifically the aromatase inhibitor (AI) letrozole at 2.5 mg/day) alone or in combination with a 25, 50, or 100 μg/day transdermal estradiol patch in the gonadally intact cisgender men. The aromatase inhibitor was included to prevent aromatization of testosterone into estradiol in the pituitary gland for purposes related to investigation of the HPG axis. The paper reported estradiol (E2), testosterone (T), gonadotropin, and sex hormone-binding globulin (SHBG) levels in its results. The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and SHBG, were measured using luminescence-based immunoassays (LIA), while estradiol and testosterone levels were measured using radioimmunoassays (RIA). The sample was 10 healthy young gonadally intact cisgender men of age 25.9 ± 6.47 years and BMI 24.75 ± 2.82 kg/m².

The study was a repeated measures design, so the same 10 cisgender men were exposed to all of the different treatment levels during different time periods. Here is the treatment schedule:

Blood tests were performed on day 0 and on the last day of each week.

Results

Here are the results of the study in the gonadally intact cisgender men with changes relative to baseline:

Notes: Values are mean ± SD. * Mean change columns are relative to baseline levels.

And here are the results of the study with changes relative to an aromatase inhibitor alone:

Notes: Values are mean ± SD. * Mean change columns are relative to AI alone.

Here is a graphical presentation of the results of the study in terms of absolute levels only:

Discussion

This study found that even relatively low doses and levels of estradiol (30–70 pg/mL [110–257 pmol/L]), delivered with transdermal estradiol patches (25–100 μg/day), considerably suppressed testosterone levels in gonadally intact cisgender men. Testosterone levels were suppressed with a 25, 50, or 100 μg/day estradiol patch in combination with an aromatase inhibitor by about 30 to 80% (to about 660 ng/dL (22.9 nmol/L), 340 ng/dL (11.8 nmol/L), and 180 ng/dL (6.2 nmol/L), respectively) relative to an aromatase inhibitor alone. The testosterone suppression at the estradiol patch dose of 100 μg/day was 64% relative to baseline (i.e., with no aromatase inhibitor).

For comparison, other studies have found that two to four 100 μg/day estradiol patches, resulting in estradiol levels of about 185 pg/mL (679 pmol/L) or more, are sufficient to achieve female/castrate levels of testosterone (≤50 ng/dL [≤1.7 nmol/L]) in cisgender men with prostate cancer (Ockrim et al., 2003; Ockrim et al., 2004; Ockrim, Lalani, & Abel, 2006; Langley et al., 2008; Langley et al., 2013; Gilbert et al., 2016; Langley et al., 2016; Graph). This lines up closely with studies on injectable polyestradiol phosphate, a long-lasting prodrug of estradiol (Stege et al., 1988; Stege et al., 1996; Graph).

An important consideration is that the brand of estradiol patch appears to influence estradiol levels and hence testosterone suppression, with some patch brands achieving lower estradiol levels and inadequate testosterone suppression (Langley et al., 2008; Langley et al., 2015). In addition to total testosterone levels, studies have shown that estradiol patches dose-dependently increase SHBG levels and hence decrease free testosterone levels, with the free testosterone fraction being unusually low at high estradiol levels (Purnell et al., 2005; Bland et al., 2005; Smith et al., 2019). This is important as only or mainly free testosterone is thought to be biologically active (Hammond et al., 2016), However, the issue of free testosterone harbors controversies (Goldman et al., 2017; Handelsman, 2017).

Estradiol levels with transdermal estradiol patches were a little low in the present study compared to levels typical with estradiol patches in cisgender women. A single 100 μg/day estradiol patch gives estradiol levels of about 100 pg/mL (367 pmol/L) on average, although with wide variability (Wiki; Graphs). Conversely, a single 100 μg/day estradiol patch gave mean estradiol levels of only about 70 pg/mL (257 pmol/L) in this study. There are a variety of possible reasons for this relating to study methodology. In any case, if estradiol levels were unusually low with the estradiol patches in this study, then testosterone suppression might be even greater with the same estradiol doses typically.

It is important to note that due to the concomitant use of an aromatase inhibitor, testosterone suppression with the specific estradiol levels in this study may have been underestimated to some degree. This is because testosterone is aromatized locally into estradiol in the pituitary gland and this has been found to be partially responsible for the inhibition of the HPG axis by testosterone in cisgender men (Pitteloud et al., 2008; Kicman, 2009; McQuaid & Tanrikut, 2014). As such, if there had not been aromatase inhibition in this study, testosterone levels might have been even lower. Indeed, the present study found that testosterone levels were about 30% higher with the aromatase inhibitor plus 25 μg/day estradiol patch relative to baseline (657 ng/dL [22.8 nmol/L] vs. 501 ng/dL [17.4 nmol/L]) despite the fact that estradiol levels were about the same (30 pg/mL [110 pmol/L] vs. 29 pg/mL [106 pmol/L]). However, some of the findings on this topic are conflicting, and the authors of the present study actually reported in their first paper that analysis of their results did not support the idea that pituitary aromatization of testosterone into estradiol is involved in the suppressive effects of testosterone on the HPG axis (Raven et al., 2006).

The considerable suppression of testosterone levels in this study even with relatively low estradiol levels is in accordance with a recent dose-ranging study of oral estradiol in transgender women (Leinung, Feustel, & Joseph, 2018; Graph). Conversely however, other studies have reported less favorable influences of lower estradiol levels on testosterone levels (Stege et al., 1988; Stege et al., 1996; Graph; Jain, Kwan, & Forcier, 2019; Aly, 2019). For instance, a study using polyestradiol phosphate in cisgender men with prostate cancer found that testosterone levels were about 260 ng/dL (9.0 nmol/L) when estradiol levels were about 130 pg/mL (477 pmol/L) (Graph), which is very different from the results of the present study (e.g., testosterone levels of about 180 ng/dL (6.2 nmol/L) with estradiol levels of only about 70 pg/mL (257 pmol/L)). The reason for the discrepancies between studies is unclear. Only further studies, ideally with the most accurate blood tests (e.g., LC–MS), can clarify this issue.

Conclusions

Taken together, the findings of the present study suggest that even low estradiol levels may considerably suppress testosterone levels in people with testes. Although the testosterone levels observed are still well above the female/castrate range (which is <50 ng/dL [<1.7 nmol/L]), and hence are not sufficient for full testosterone suppression, combination with an antiandrogen or progestogen can block or suppress the remaining testosterone and hence allow for a fully effective hormonal transition. In any case, whereas data from studies of higher estradiol levels and testosterone suppression are more uniform (i.e., testosterone levels of consistently ≤50 ng/dL [≤1.7 nmol/L] with estradiol of ≥200 pg/mL [734 pmol/L]), data for lower estradiol levels are more conflicting at present, and hence should be considered with caution. Practically speaking, higher levels of estradiol could prove to be required to attain the same testosterone suppression that was reported in the present study. This emphasizes the need for blood work and dosage adjustment of estradiol as well as antiandrogens as necessary.

Addendum

Another similarly designed study, this one in post-gonadectomy transfeminine people, was also published subsequently by the same group of researchers:

• Ten Kulve, J. S., de Jong, F. H., & de Ronde, W. (2011). The effect of circulating estradiol concentrations on gonadotropin secretion in young and old castrated male-to-female transsexuals. The Aging Male, 14(3), 155–161. [DOI:10.3109/13685538.2010.511328]

This study of course does not have useful data on testosterone suppression as the transfeminine people were post-gonadectomy. But it does have data on suppression of the gonadotropins with different transdermal estradiol patch doses, which is notable and still useful.

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