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

By Aly W. | First published April 3, 2020 | Last modified October 5, 2020

Introduction

Estrogens dose-dependently suppress testosterone levels in gonadally intact people assigned male at birth, such as cisgender males and transfeminine people (Wiki; Wiki-Graphs; Aly W., 2018; Aly W., 2019; Aly W., 2019). We have data showing testosterone suppression for oral estradiol, sublingual estradiol, transdermal estradiol, and injections of estradiol esters. Much of this data is for relatively high estradiol levels however (e.g. >200 pg/mL). The data on testosterone suppression with lower estradiol levels, particularly with transdermal estradiol, aren’t 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 transgender women:

  • 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 men. 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’d share and discuss their findings.

Methodology

The results of the two studies in the gonadally intact men were very similar and seem to have been largely the same individuals and set of data, so I’ll only describe the results presented in the more recent paper. In addition, I’ll only describe the paper in relation to the gonadally intact men, since the gonadectomized transgender women in the study had low baseline testosterone levels and hence provided no direct information on testosterone suppression with transdermal estradiol patches.

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 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 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 men were exposed to all of the different treatment levels during different time periods. Here is the treatment schedule:

TimeRegimen
Day 0 (baseline)No medications
Week 1 (days 1–7)Letrozole 2.5 mg/day
Week 2 (days 7–14)Letrozole 2.5 mg/day + 1x transdermal estradiol patch 100 μg/day
Week 3 (days 14–21)Letrozole 2.5 mg/day + 1x transdermal estradiol patch 50 μg/day
Week 4 (days 21–28)Letrozole 2.5 mg/day + 1x transdermal estradiol patch 25 μg/day

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 men with changes relative to baseline:

RegimenE2 levelsMean E2 change*T levelsMean T change*
Baseline29 ± 8 pg/mL501 ± 97 ng/dL
AI + E2 0 μg/day13 ± 7 pg/mL-16 pg/mL (-57%)954 ± 291 ng/dL+453 ng/dL (+90%)
AI + E2 25 μg/day30 ± 12 pg/mL+1 pg/mL (+4%)657 ± 196 ng/dL+156 ng/dL (+31%)
AI + E2 50 μg/day44 ± 18 pg/mL+15 pg/mL (+52%)340 ± 89 ng/dL-161 ng/dL (-32%)
AI + E2 100 μg/day69 ± 38 pg/mL+40 pg/mL (+137%)179 ± 91 ng/dL-322 pg/mL (-64%)

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:

RegimenE2 levelsMean E2 change*T levelsMean T change*
AI + E2 0 μg/day13 ± 7 pg/mL954 ± 291 ng/dL
AI + E2 25 μg/day30 ± 12 pg/mL+17 pg/mL (+131%)657 ± 196 ng/dL-297 ng/dL (-31%)
AI + E2 50 μg/day44 ± 18 pg/mL+31 pg/mL (+238%)340 ± 89 ng/dL-614 ng/dL (-64%)
AI + E2 100 μg/day69 ± 38 pg/mL+56 pg/mL (+431%)179 ± 91 ng/dL-775 pg/mL (-81%)

Notes: Values are mean ± SD. * Mean change columns are relative to AI + E2 0 μg/day.

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), delivered with transdermal estradiol patches (25–100 μg/day), considerably suppressed testosterone levels in gonadally intact people assigned male at birth. 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, 340, and 180 ng/dL, respectively) relative to an aromatase inhibitor alone. The testosterone suppression at 100 μg/day was 64% relative to baseline (i.e., no aromatase inhibitor).

For comparison, other studies have found that 2 to 4x 100 μg/day estradiol patches, resulting in estradiol levels of about 185 pg/mL or more, are sufficient to achieve female/castrate levels of testosterone (≤50 ng/dL) in 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; Wiki-Graph). This lines up closely with studies on intramuscular injections of polyestradiol phosphate, a long-lasting prodrug of estradiol (Stege et al., 1988; Stege et al., 1996; Wiki-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 on average, although with wide variability (Wiki; Wiki-Graphs). Conversely, a single 100 μg/day estradiol patch gave mean estradiol levels of only about 70 pg/mL 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’s important to note that due to the concomitant use of an aromatase inhibitor, testosterone suppression with the specific estradiol levels in this study might have been underestimated. 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 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 ± 196 ng/dL vs. 501 ± 97 ng/dL) despite the fact that estradiol levels were about the same (30 ± 12 pg/mL vs. 29 ± 8 pg/mL). 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; Wiki-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; Wiki-Graph; Jain, Kwan, & Forcier, 2019; Aly W., 2019). For instance, a study using polyestradiol phosphate in men with prostate cancer found that testosterone levels were about 260 ng/dL when estradiol levels were about 130 pg/mL (Wiki-Graph), which is very different from the results of the present study (e.g., testosterone levels of about 180 ng/dL with estradiol levels of only about 70 pg/mL). The reason for the discrepancies between studies is unclear. Only further studies, ideally with the most accurate blood work methodologies (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 assigned male at birth. Although the testosterone levels observed are still well above the female/castrate range (which is <50 ng/dL), and hence aren’t sufficient for full testosterone suppression, combination with an antiandrogen like bicalutamide can block 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 with estradiol of ≥200 pg/mL), 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 doesn’t have useful data on testosterone levels. But it does have data on suppression of the gonadotropins with different transdermal estradiol patch doses.