Supplement: The Interactions of Sex Hormones with Sex Hormone-Binding Globulin and Relevance for Transfeminine Hormone Therapy
By Aly | First published July 8, 2020 | Last modified March 14, 2023
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 content to it as well.
Calculation of Free Hormone Levels
Spreadsheet Calculator (Mazer, 2009)
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. Because of this, I’ve uploaded a copy of the original spreadsheet here (Microsoft Excel or XLS format).
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.
Some Experimentation with the Calculator
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:
| SHBG | Estradiol fixed ≤1,000 pg/mL | Estradiol fixed 20,000 pg/mL | |||
|---|---|---|---|---|---|
| Level | Change a | Free E2 fraction | Change a | Free E2 fraction | Change a |
| 0 nmol/L | 0.0× | 3.26% | +77.2% | 3.26% | +37.0% |
| 25 nmol/L | 0.5× | 2.36% | +28.3% | 2.78% | +16.8% |
| 50 nmol/L | 1.0× | 1.84% | 0% | 2.38% | 0% |
| 75 nmol/L | 1.5× | 1.50% | –18.5% | 2.04% | –14.3% |
| 100 nmol/L | 2.0× | 1.27% | –31.0% | 1.77% | –25.6% |
| 125 nmol/L | 2.5× | 1.10% | –40.2% | 1.54% | –35.3% |
| 150 nmol/L | 3.0× | 0.97% | –47.3% | 1.36% | –42.9% |
| 200 nmol/L | 4.0× | 0.79% | –57.1% | 1.08% | –54.6% |
| 250 nmol/L | 5.0× | 0.66% | –64.1% | 0.89% | –62.6% |
| 300 nmol/L | 6.0× | 0.57% | –69.0% | 0.75% | –68.5% |
| 350 nmol/L | 7.0× | 0.50% | –72.8% | 0.65% | –72.7% |
| 400 nmol/L | 8.0× | 0.44% | –76.1% | 0.57% | –76.1% |
a Change relative to a reasonable non-pregnancy physiological value (specifically 50 nmol/L 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 Papers on Calculation of Free Hormone Levels
Aside from Mazer (2009), other papers like Vermeulen, Verdonck, & Kaufman (1999) and Rinaldi et al. (2002) also discuss calculation of free sex hormone levels and the validity of this approach.
Other Online Free Hormone Calculators
Another tool for calculating free estradiol and testosterone can be found here. Various other free testosterone calculators also exist on the web (Google Search).
Additional Literature on SHBG and Free Estradiol
Additional SHBG and Free Estradiol Clinical Studies
Some more good studies on SHBG and free estradiol that weren’t discussed in the main article:
- Odlind et al. (1982) – various forms of estrogen on SHBG in cis women
- Ben-Rafael et al. (1986) [Table] – gonadotropin stimulation in cis women
- Carlström, Pschera, & Lunell (1986) [Excerpt] – vaginal estradiol in cis women + review
- Jasonni et al. (1988) [Excerpt] – transdermal estradiol in cis women + review
- Elaut et al. (2008) [Table] – various estrogens in transfeminine people
- Lapauw et al. (2008) [Table] – various estrogens in transfeminine people
- Nelson et al. (2016) [Table] – mainly high-dose injectable estradiol in transfeminine people
Miscellaneous
A case report of a young woman with estrogen insensitivity syndrome (EIS) (i.e., defective ERα) suggests that the ERα is the specific estrogen receptor that is responsible for increased SHBG production and levels with estrogens (Quaynor et al., 2013). Due to her EIS and lack of negative feedback on the hypothalamus–pituitary–gonadal axis, the woman had estradiol levels of as high as 3,500 pg/mL. In spite of this however, her SHBG levels remained less than 50 nmol/L. During pregnancy, at the point in the second trimester at which estradiol levels reach 3,000 pg/mL, SHBG levels are normally around 300 nmol/L on average (a 6-fold increase from a pre-pregnancy baseline of about 50 nmol/L).
References
- Ben-Rafael, Z., Mastroianni, L., Meloni, F., Strauss, J. F., & Flickinger, G. L. (1986). Changes in serum sex hormone-binding globulin, free estradiol, and testosterone during gonadotropin treatment. Fertility and Sterility, 46(4), 593–598. [DOI:10.1016/s0015-0282(16)49633-0]
- Carlström, K., Pschera, H., & Lunell, N. (1988). Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17β-oestradiol and progesterone in the pre- and post-menopause. Maturitas, 10(4), 307–316. [DOI:10.1016/0378-5122(88)90066-7]
- Elaut, E., De Cuypere, G., De Sutter, P., Gijs, L., Van Trotsenburg, M., Heylens, G., Kaufman, J., Rubens, R., & T’Sjoen, G. (2008). Hypoactive sexual desire in transsexual women: prevalence and association with testosterone levels. European Journal of Endocrinology, 158(3), 393–399. [DOI:10.1530/eje-07-0511]
- Jasonni, V., Bulletti, C., Naldi, S., Ciotti, P., Di Cosmo, D., Lazzaretto, R., & Flamigni, C. (1988). Biological and endocrine aspects of transdermal 17β-oestradiol administration in post-menopausal women. Maturitas, 10(4), 263–270. [DOI:10.1016/0378-5122(88)90062-x]
- Lapauw, B., Taes, Y., Simoens, S., Van Caenegem, E., Weyers, S., Goemaere, S., Toye, K., Kaufman, J., & T’Sjoen, G. G. (2008). Body composition, volumetric and areal bone parameters in male-to-female transsexual persons. Bone, 43(6), 1016–1021. [DOI:10.1016/j.bone.2008.09.001]
- 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]
- Nelson, M. D., Szczepaniak, L. S., Wei, J., Szczepaniak, E., Sánchez, F. J., Vilain, E., Stern, J. H., Bergman, R. N., Bairey Merz, C. N., & Clegg, D. J. (2016). Transwomen and the Metabolic Syndrome: Is Orchiectomy Protective? Transgender Health, 1(1), 165–171. [DOI:10.1089/trgh.2016.0016]
- Odlind, V., Elamsson, K., Englund, D. E., Victor, A., & Johansson, E. D. (1982). Effects of oestradiol on sex hormone binding globulin. Acta Endocrinologica, 101(2), 248–253. [DOI:10.1530/acta.0.1010248] [PDF]
- Quaynor, S. D., Stradtman, E. W., Kim, H., Shen, Y., Chorich, L. P., Schreihofer, D. A., & Layman, L. C. (2013). Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant. New England Journal of Medicine, 369(2), 164–171. [DOI:10.1056/nejmoa1303611]
- Rinaldi, S., Geay, A., Déchaud, H., Biessy, C., Zeleniuch-Jacquotte, A., Akhmedkhanov, A., Shore, R. E., Riboli, E., Toniolo, P., & 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. [Google Scholar] [PubMed] [URL]
- 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]