Disclaimer: I am not a medical professional and this is not medical advice.
I’ve previously covered anecdotal reports from HRT provider Dr. Will Powers on the role of relative levels of different kinds of estrogens in producing effective physical feminization in trans women. Estrogen is not one thing; estradiol (E2), the most common estrogen used in trans women’s HRT, is just one kind. Another form of estrogen, estrone (E1), binds to estrogen receptors but is much weaker in its effects than estradiol, and excessive levels of estrone compared to estradiol can crowd out estradiol at these receptors, inhibiting its feminizing effects. However, lab tests for trans women’s estrogen levels often only measure estrogen as a whole, rather than estradiol and estrone separately. Because of this, what appear to be adequate levels of estrogen may in reality consist mostly of less effective estrone rather than estradiol.
Powers has generally recommended the use of estradiol by depot injection rather than oral tablets to produce greater levels of estradiol and lower levels of estrone, and reports that this approach has resulted in more effective feminization for many of his trans women patients. A recent conference presentation by Robert Francis Mijares (2019) offers additional data comparing the observed estradiol/estrone ratios of trans women taking HRT via different routes of administration. Based on a retrospective chart review of 72 trans women patients and their 88 lab results specifically measuring estradiol and estrone levels, Mijares examined the estradiol/estrone ratios produced by oral, sublingual, injection, transdermal (patch), and implanted pellet forms of prescription estradiol:
Only injectable, transdermal, and pellet forms of estradiol produced estradiol/estrone ratios considered to be in a normal range, with estrone consisting of 33% or less of total estrogen. Conversely, oral estradiol resulted in overall levels consisting of 77.5% estrone, and even sublingual administration produced estrone levels of 66.1%.
Mijares additionally cites Girdler et al.’s (2004) finding that transdermal estradiol produced “serum estradiol/estrone ratio closer to premenopausal values” in postmenopausal women, compared to those taking oral estradiol, as well as Bagot et al.’s (2010) study suggesting that the greater estrone levels caused by oral estradiol use may account for its greater risk of blood clots compared to transdermal estradiol:
Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first‐pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.
Goldstein et al. (2019) further observed that transdermal estradiol may be safer for trans women than other forms of estradiol, and that the first-pass metabolism of oral estradiol increases the risk of blood clots in a number of ways:
It is now thought that the method of estrogen administration impacts VTE outcomes. The ESTHER (Estrogen and Thromboembolism Risk) study suggested that oral, but not transdermal, estradiol increases the risk of VTE in postmenopausal women. Oral estrogens have a significant first-pass effect, which is possibly what causes their disproportionate thrombogenic effects. Oral estrogen increases levels of factor VII, factor VIII, factor X, prothrombin, and fibrinogen, and decreases antithrombin and protein S.
The use of forms of estradiol other than oral tablets is not only a matter of more effective treatment for gender dysphoria, but safer treatment as well. Unfortunately, the United States has experienced disruptive shortages of both name-brand and generic injectable estradiol in 2014, 2016, and most recently in 2018, forcing some trans women to switch back to pills. As the Callen-Lorde Community Health Center noted in 2016:
Patients who go from patches to injectables notice more significant changes. Patients have mostly positive experiences with injectable estrogen, which causes them to view pills and patches as second-tier options. Therefore, injectable estrogen is a necessary product for the health and wellbeing of transgender women.
I’m hopeful that more research will be conducted into the role of estradiol/estrone ratios in feminization for trans women and how this can be most effectively and safely managed. But for that evidence to be actionable, trans women need to be able to access these necessary medications in the first place. ■
