Yesterday morning I got a call from a nurse at my doctor’s office to tell me my most recent round of lab results. I was surprised when the call was cheerily punctuated with, “Remember, too much estrogen converts to testosterone and undoes your changes!”.
Countless transgender women have been told the same thing by their HRT prescribers, usually in the same breath as instructions to lower their dosages. Because statements like this leverage anxiety and gender dysphoria, they are extremely persuasive, especially when coming from a place of perceived authority. They have caused many trans women I know personally severe distress and contributed to a feeling of futility in their biomedical transitions, as well as the potential harm of questionably low-dose hormone regimens.
Unlike most transgender women, however, I’m lucky to have had enough education to know this for what it is: not accurate medical information, but a scare tactic meant to dissuade people from deliberate overdose or self-medication.
There is no known pathway for testosterone biosynthesis from estrogens.
Put simply, this just does not occur. We know of no enzyme that “converts” excess estradiol to testosterone.
The opposite process, biosynthesis of estradiol from testosterone, does occur in people regardless of birth assignment through the enzyme aromatase, also called estrogen synthase. This raises the question of whether an abundance of exogenous estradiol could force the reaction to proceed in reverse. This does not, however, appear to be the case.
Aromatase functions through a three-step mechanism involving successive oxidations of testosterone’s C19 methyl group, followed by eliminative aromatization to estradiol [1][2].
A detailed mechanistic study found that, while some steps of the catalysis occur in equilibrium even at typical concentrations, aromatase cannot effectively catalyze the reverse reaction even in an abundance of product; while the estrogenic product binds weakly to aromatase, the rate constant of the reverse reaction was too small to be measured and the conversion from androgenic to estrogenic product may be considered one-directional [2]. I would speculate that this owes partially to aromatization energy (in essence, estradiol is a more stable molecule than testosterone), but that’s just a guess.
So, while it is demonstrably false that estrogen can be “converted” to testosterone, we might still assume that practitioners who tell this to patients are acting in good faith, and merely simplifying a different process. This raises another question:
Can estradiol overdose increase testosterone synthesis? Maybe. Should trans women be concerned? No.
It’s been known since the mid-’70s that high levels of endogenous estadiol (E2) exert positive feedback on the release of gonadotropin-releasing hormone (GnRH) [3]. This is, in fact, a major part of the ovulation cycle. Additionally, through the hypothalamic-pituitary-gonadal axis, these GnRH pulses trigger the release of luteinizing hormone (LH), which in turn regulates testosterone synthesis in the Leydig cells of the testes.
It’s possible, then, to imagine a scenario in which highly elevated levels of exogenous serum estradiol—in the case of, say, an accidentally-doubled intramuscular dose—engage the positive feedback loop of the HPG axis, triggering a surge in testosterone production. As best I can tell, this is speculative and has not yet been clinically observed in transgender women on HRT. Similar phenomena called ‘testosterone flares’, however, have been observed during the administration of GnRH and LH agonists for prostate cancer [4]. These flares last only 1 to 3 weeks [4], however, because sustained engagement of the HPG axis positive feedback loop desensitizes the system [5].
None of this, however, should present a concern for trans women on HRT. This is because testosterone flare will not affect anyone under androgen-receptor blockade by cyproterone acetate or bicalutamide [4], nor will it affect anyone whose testosterone biosynthesis has been externally suppressed by drugs like spironolactone [6] or by surgery like orchiectomy.
Moreover, because LH only regulates Leydig cell testosterone secretion, HPG axis positive feedback will have no effect on adrenal testosterone synthesis—a separate process regulated by corticotropin and CRH.
Practitioners who repeat this myth to trans patients might actually believe it, but their patients shouldn’t have to!
[N.B. I am not an endocrinologist. I am a trans person and former research chemist, primarily trained in chemical biology. This post contains information gathered from the biochemical literature, and does not constitute medical advice.]
References
J Am Chem Soc; 136, 15016−15025.
[4] Thompson IM (2001). Flare associated with LHRH-agonist therapy.
Rev Urol; 3(Suppl 3): S10–S14.
[6] Corvol P (1975). Antiandrogenic effect of spirolactones: mechanism of action.
Endocrinology; 97(1):52-8.
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The opposite process, biosynthesis of estradiol from testosterone, does occur in people regardless of birth assignment through the enzyme aromatase,
also called estrogen synthase. This raises the question of whether an
abundance of exogenous estradiol could force the reaction to proceed in
reverse. This does not, however, appear to be the case.“does this mean that trans men need to be concerned about excess testosterone synthesizing into estrogen? because if that’s the case, it sounds like the problem is people assuming it goes both ways, or accidentally getting it backwards, rather than deliberately trying to scare trans women.
Yes. Excess testosterone converts to estrogen. Before I switched to Costco, my Walgreens pharmacy wrote my dosage as double what my doctor had sent without my knowledge.
(my doctor sends the prescription to the pharmacy, and I don’t get a copy if I don’t ask for it) (I had just started HRT and assumed that I had misunderstood my doctor on the dosage and didn’t question it.)
Over the course of the next 4 months, I suffered a lot as a result of having far too high of estrogen. Extreme depression, extreme periods, and some other physical malfunctions I’d rather not discuss. I ended up basically bedridden and lost my job. I still have $1,200 in medical debt because of it. It didn’t occur to me that it could be a dosage issue because I’m dense, and I was too poor to see a doctor.
Verify with your doctor the correct dosage before taking it, and stick to that. If something seems off, consult your doctor. Typically if it’s just about changing the dosage, it can be a phone call rather than an appointment, and you shouldn’t be charged doctor fees.
Stay safe.
Dispelling HRT scare tactics: Excess estrogen does not “convert” to testosterone
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