Many trans men on HRT may not show testosterone levels in the “target range” – and that can be okay

Disclaimer: I am not a medical professional and this is not medical advice.

Blood tests and monitoring are a standard component of prescribed feminizing or masculinizing hormone therapy, with these tests typically including measurements of testosterone levels and estrogen levels taken every three months in the first year and once yearly after this (Hembree et al., 2017). These measurements are intended to help adjust dosing so that trans women achieve estrogen and testosterone levels within a typical female range, and trans men achieve levels within a typical male range. But while the concept of this is straightforward, in practice there are still questions about how best to carry this out: What are the actual ranges that should be aimed for? And how much does it matter, in terms of the effectiveness of treatment, whether those ranges are attained?

A recent study by Greene et al. (2020) takes a descriptive rather than prescriptive approach, measuring the sex hormone levels of a cohort of 82 trans men who had been taking testosterone for at least a year, and analyzing the distribution of testosterone and estrogen levels that they achieve. This analysis serves to establish empirical laboratory reference intervals for sex hormone levels in trans men, a range of values that consists of the middle 95% of values of a given measurement in a healthy population. This range is used to establish whether a particular patient’s levels are considered to be “normal” (less than 2 standard deviations from the mean).

What the authors found surprisingly differed from the target ranges for testosterone levels in trans men given by medical organizations such as the Endocrine Society. For example, the Endocrine Society’s 2017 clinical guidelines for transgender HRT recommend that trans men maintain “testosterone levels in the physiologic normal male range”, a range which is given as 400–700 ng/dL. In the present study, authors used three different instruments to establish the middle 95% reference range of total testosterone levels in this sample of trans men, finding ranges of 158-1115 ng/dL, 180-930 ng/dL, and 199-1149 ng/dL.

It’s clear that among these trans men, a substantial portion have test results for testosterone levels that are outside the “target range” of 400-700 ng/dL. Just how many? The authors go on to break down the measured levels by quartile, finding that for each of the three instruments used, the middle 50% of testosterone levels ranged from 318-656 ng/dL, 320-630 ng/dL, and 360-710 ng/dL. Essentially, the guideline of “400-700 ng/dL” may be representative of the measured testosterone levels of only about half of trans men on HRT, and does not represent a laboratory reference range as traditionally constructed. A trans man could receive a result showing his testosterone level is less than 400 or greater than 700 ng/dL, yet it would still be likely that he does fall within the normal reference range for testosterone levels in trans men.

That’s not all – the authors go on to point out that the “400-700 ng/dL” guideline is not necessarily representative of normal testosterone levels among healthy cis men:

However, aiming for the guideline-recommended 400–700 ng/mL [sic] may be too tight of a range, as most reference intervals for cisgender men are much wider on both the lower and upper ends.

How much wider? Contrast the reference ranges for total testosterone levels in adult men listed for six different instruments (Wang et al., 2004):

• HUMC-RIA: 298–1043 ng/dL
• DPC-RIA: 250–900 ng/dL
• Roche Elecsys: 210–810 ng/dL
• Bayer Centaur: 241–827 ng/dL
• Ortho Vitros ECi: 132–813 ng/dL
• DPC Immulite 2000: 286–1510 ng/dL

These are indeed much wider ranges for what is considered normal testosterone in adult cis men. For example, even before I started HRT, my testosterone was measured at 346 ng/dL; under the “400-700 ng/dL” guideline, if I were a trans man, I clearly needed more testosterone. Do trans men whose levels are outside that conventional range require a change of dose? The authors note that this may not be necessary:

Trying to titrate the serum testosterone concentration to between 400–700 ng/mL [sic] is unforgiving for the timing of the serum test relative to the IM [intramuscular] dose, likely leading to frustrations for both the patient and provider.

This is an important point. While trans women may commonly take oral HRT at least once daily, oral preparations of testosterone are not common, and trans men frequently take testosterone in the form of long-acting injections every week or two weeks (or even a month or three months for longer-acting preparations). This raises the question of when, in the period between one injection and the next, testosterone levels should be measured. Even the WPATH Standards of Care are unclear on this point, simply noting that “some clinicians check trough [lowest point] levels while others prefer midcycle levels”. As the authors highlight, this means that a test result below 400 ng/dL may not actually indicate that a trans man isn’t nevertheless at levels between 400-700 ng/dL at most times. An increase of dose based on that test result might therefore lead to prescribing more testosterone than that man actually needs for effective treatment.

And what’s actually effective, in terms of clinical assessment, should weigh more heavily in treatment considerations – a simple number is not the final word for the purposes of clinical decision-making. As WPATH notes, “The best assessment of hormone efficacy is clinical response: Is a patient developing a masculinized body while minimizing feminine characteristics, consistent with that patient’s gender goals?” This same consideration has been pointed out by others in the context of feminizing HRT (Liang et al., 2018), as spironolactone may serve to occupy the androgen receptor, meaning that it can block the action of testosterone and help to achieve feminization and demasculinization even if it does not substantially reduce circulating testosterone levels. This is an aspect of assessment I’ve undergone as well, with my physician observing that I’d had notable breast development and skin softening even as my testosterone levels were slightly above the typical cis female range and my estrogen levels were slightly below it. And this was precisely the clinical outcome we were looking to achieve – it was not inadequate or unsatisfying because of measured blood levels. As the present study notes, the same applies to trans men, and the current narrow guidelines for testosterone levels can’t tell the whole story. ■