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Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance to Transfeminine People

By Aly W. | First published July 8, 2020 | Last modified December 21, 2020

Preface

This article is a supplement to the article here. It was originally just for calculation of free sex hormone levels but I decided to add some other additional content to it as well.

Spreadsheet Calculator

A researcher developed and published a “user-friendly” spreadsheet that can be used to calculate free and bioavailable levels of several steroid hormones (Mazer, 2009). This spreadsheet approach is analogous to how free hormone levels are calculated with actual conventional blood work. Total hormone levels and levels of plasma proteins like albumin and SHBG are taken as inputs by the spreadsheet, and free and bioavailable hormone levels are given as outputs.

The spreadsheet is supplementary material for Mazer (2009) and is behind a paywall. Consequently, I’ve uploaded a copy of the original spreadsheet here (XLS) and have converted the spreadsheet to Google Sheets format here. Free hormone percentages weren’t calculated in the original spreadsheet, so for convenience I added automatic calculation of those percentages for estradiol, testosterone, and DHT to the Google Sheets version. In order to use the Google Sheets version of the spreadsheet yourself and provide your own inputs, you’ll need to make a copy of mine.

If you’re curious how SHBG may be influencing your free estradiol percentage, you can use the spreadsheet to get an estimate. If you don’t have albumin, CBG, or cortisol values, you can use the default input values in the spreadsheet. If you don’t have other input values (e.g., estrone or SHBG), you can input representative values that are sensible for your scenario. It should be noted that calculated free hormone levels are only estimates and hence can be inaccurate. In any case, they are generally fairly close to the values that would be obtained with actual measurement. Use of default input values as opposed to real measured numbers may further contribute to inaccuracy.

Experimentation

Here are the results of some experimentation I did with the calculator:

Table: Relationships between SHBG levels and calculated free estradiol fraction at fixed estradiol levels:

SHBGEstradiol fixed ≤1,000 pg/mLEstradiol fixed 20,000 pg/mL
LevelChange aFree E2 fractionChange aFree E2 fractionChange a
0 nM0.0×3.26%+77.2%3.26%+37.0%
25 nM0.5×2.36%+28.3%2.78%+16.8%
50 nM1.0×1.84%0%2.38%0%
75 nM1.5×1.50%–18.5%2.04%–14.3%
100 nM2.0×1.27%–31.0%1.77%–25.6%
125 nM2.5×1.10%–40.2%1.54%–35.3%
150 nM3.0×0.97%–47.3%1.36%–42.9%
200 nM4.0×0.79%–57.1%1.08%–54.6%
250 nM5.0×0.66%–64.1%0.89%–62.6%
300 nM6.0×0.57%–69.0%0.75%–68.5%
350 nM7.0×0.50%–72.8%0.65%–72.7%
400 nM8.0×0.44%–76.1%0.57%–76.1%

a = Change relative to a reasonable non-pregnancy physiological value (specifically 50 nM for SHBG, 1.84% for free E2 at a fixed level of ≤1,000 pg/mL, 2.38% for free E2 at a fixed level of 20,000 pg/mL).

Androgen levels were set to female levels, estrone levels were set to be the same as estradiol levels, and all other inputs besides SHBG and total estradiol levels were left as the defaults. There was very little variation in free estradiol fractions with different estradiol levels at and below 1,000 pg/mL for each given level of SHBG (hence why the table says “Estradiol fixed ≤1,000 pg/mL”).

The estradiol levels fixed to ≤1,000 pg/mL are intended to represent typical therapeutic circumstances while the estradiol levels fixed to 20,000 pg/mL are supposed to represent late pregnancy.

Note that since estradiol induces SHBG production, SHBG levels are strongly correlated with estradiol levels. Generally speaking, when estradiol is low, SHBG will also be low, and when estradiol is high, SHBG will also be high. Hence, having highly divergent SHBG and estradiol levels as in the table would be very unusual and is physiologically unrealistic. It is only explored here as a thought experiment.

Note again that these free estradiol numbers are calculated and hence are only estimates.

Other Calculators

Another method of calculation can apparently be found here and here (direct link here).

Papers on Calculation of Free Estradiol and Testosterone

  • Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. The Journal of Clinical Endocrinology & Metabolism, 84(10), 3666–3672. [DOI:10.1210/jcem.84.10.6079]
  • Rinaldi, S., Geay, A., Déchaud, H., Biessy, C., Zeleniuch-Jacquotte, A., Akhmedkhanov, A., … & Kaaks, R. (2002). Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiology and Prevention Biomarkers, 11(10), 1065–1071. [URL]
  • Mazer, N. A. (2009). A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: with illustrative examples from male and female populations. Steroids, 74(6), 512–519. [DOI:10.1016/j.steroids.2009.01.008]

Additional Content

Additional Free Estradiol Clinical Studies

Some more good free estradiol clinical studies that weren’t discussed in the main article:

Calculated Free Estradiol in First Trimester of Pregnancy

The O’Leary et al. (1991) x Mazer (2009) pregnancy graph with calculated free estradiol rescaled to the first trimester of pregnancy only (when estradiol levels are typically ≤2,000 pg/mL):

Average measured total estradiol and SHBG levels (O’Leary et al., 1991) and calculated free estradiol percentage (Mazer, 2009) throughout the first trimester of pregnancy in women.

As with the original whole pregnancy version from the main SHBG article, the free estradiol values are calculated so take the free estradiol curve with a grain of salt.

Miscellaneous

ERα activation is responsible for SHBG increases with estrogens: Quaynor et al. (2013) [Table]