Anti-androgens: spironolactone and bicalutamide

[NOTE: This essay was updated March 24th, 2021 with newer research, clarifications, style changes, and such. See footnote references inline for largest points on the former.]

When I was first considering medical transition, I hung out in a number of communities trying to make sense of the current state of trans research. It’s pretty abysmal. There are few large, well designed studies exploring treatment outcome. Many of the anti-androgen options are old, cause side effects, have potential health risks and may even work against optimal feminization.

Being the nerd I am, I felt the need to deeply educate myself before seeing a doctor about HRT. My goal was to convince them with evidence of a better way. Thankfully, there were a bunch of other trans folks thinking similarly that wanted to do research with me and share their knowledge.

Spironolactone

In the US, the anti-androgen of choice is spironolactone, a potassium-sparing diuretic once used as a blood pressure medication. If you google this drug, the first few drug info pages don’t even mention the fact that it is used in trans medicine!

Why the hell is this the preferred treatment? Well, its cheap and well known is the best answer I’ve came up with. Some people don’t have any issues on it even having taken it for years. Knowing myself and my body, I wouldn’t be one of those people and had no interest in finding out just how shitty it’d be. The draw backs to all these off-target effects were completely unacceptable to me.

It being a diuretic, it can increase urination frequency. This can lead to dehydration, or electrolyte imbalances such as hyperkalemia - excess potassium in the blood - a potentially life threatening condition. This is unlikely to happen if you know about it and compensate, and if it does, it’ll be noticed by your doctor before becoming problematic. In my case, I’m prone to depression and bad at self care at times, so I wasn’t confident I’d be able to stay hydrated and eat properly to mitigate.

Fatigue, headache, dizziness, drowsiness, and muscle/abdominal cramping are reported, but at unknown incidence. It makes sense that these would occur to some extent though, since it can reduce blood pressure and affect theoretically alter cholesterol and blood sugar levels. These are also unlikely to occur without preexisting disease that would contribute to it. I find myself hypersensitive to drugs most of the time though, and it is common for me to experience uncommon side effects. Again, my depression didn’t need any help so I was wary of the possibility of fatigue.

There are several essays on other side effects including weight gain, increased stress, brain fog, and depression that are largely unsubstantiated. I don’t even want to link them because I feel they promote fear by disinformation and poor interpretation of biochemistry. I might write something at a later date picking all of their failings apart, but for now, please be critical of people taking extremely negative stances against this drug. If you have it in you, please try to check the sources (mirror), or at least resist others’ anecdote or authoritatively presented arguments in favor of rigorous proof.

Adrenal brain tumors have been reported. The incidence and mechanistic cause of these are unknown. It is reasonable to infer based on literature account and complete lack of this being mentioned in prescribing information that it is extremely rare. Anyone stating otherwise is fear mongering and has an agenda.

Now, spironolactone is commonly considered a moderate anti-androgen when used appropriately. It requires large doses for that, though. It competes with and effectively blocks (antagonizes) androgen receptors in tissues moderately, preventing testosterone and dihydrotestosterone (DHT) from binding. This is the main known mechanism by which most of its anti-androgenic effect are derived from. There are other means by which it or its metabolites contribute - steroidogenesis and enzymatic androgen synthesis inhibition - but they are weak or compensated for by homeostasis.

[Update: Yes, I’m aware I didn’t cite a source for this, but in my defense, it is widely publicized on given the age of this medication 😅]

HOT take alert!! The goal of transfeminine hormone therapy is not necessarily to reduce serum testosterone levels to the cisfem range, contrary to what the World Professional Association for Transgender Health says!¹ Spironolactone isn’t good at this. There is high individualistic variability of response across this dimension that can’t be accounted for by modifying dosing of it or estradiol. What it is reliably effective at, is producing sex differentiation desirable by transfeminine people seeking medical intervention.

Often this is good enough to satisfy patients undergoing this regimen. Whether its optimal is subject to growing debate, as those AR antagonistic effects are potentially not biochemically strong enough to fully block remaining systemic androgens (2.7% relative binding affinity compared to DHT).

Bicalutamide

I ended up choosing, requesting and being prescribed bicalutamide as my anti-androgen. Again, this drug is uncommonly prescribed, and not recommended by any endocrinology or trans health organizations. UCSF goes so far as to say it specifically says it isn’t worth the ‘risk,’ which is totally off base! It is also not primarily indicated for transfeminine HRT, but rather prostate cancer. Why is this? That’d be due to its potency as an androgen receptor antagonist.

At steady state, after about a month of consistent daily use, its concentration is sufficient to overwhelm androgens and preferentially block their binding sites. Theoretically. At the right dose. What’s the right dose? We don’t know for sure, but upwards and beyond 100mg is used in patients with prostate cancer. This results in slowed or eliminated tumor growth, which is a good indicator.

Here’s where some speculation and inference comes in, though. It’s suspected that dose is over the top for use in a transfem HRT regimen. I’m not entirely sure why this is other than oncologists wanting to make absolute sure that they completely suppress androgens from binding, considering their doing so in a cancer state results in more cancer…

The thrust of this tactic is in co-combinant estradiol administration. That’ll lower T by pushing on the HPG axis - it being present in certain tissues signals for reduced production of gonadotropin. This in turn signals the gonads to downregulate production of androgens. So, what’s the dose to go with them? Best effort guess here is commonly 50mg.² An exception here is for an initial loading dose to expedite reaching steady state (i.e. start higher than the dose that will be maintained thereafter).

Anyway, this mechanism is likely to be all it does. Large scale initial studies performed for it to gain regulatory approval (n>1,000) concluded it had no off-target effects and a small unintended side effect profile. That’s the advantage here, and it’s rather significant when compared to spiro! The downside? Longitudinal studies (trialing for >1yr) are few. 😓 That introduces unknown risk for those who do not wish to ever pursue surgery to remove the testes, unfortunately.

There are some claims that it may degrade and destroy androgen receptors over time, but this hasn’t been widely investigated. Taken at face value, one might think this could be a positive benefit for someone seeking feminization. Realistically, I think that’s a stretch and wishful thinking.

Healthy cisgendered women have some endogenous testosterone and it is considered a disease state for this not to be the case! A natural reduction occurs in aging and unnaturally presents in adrenal insufficiency. The problem? It may result in fatigue, lowered mood, self-esteem, motivation, and/or libido. Degrading AR or fully suppressing T could mimic this.

Both drugs may rarely cause liver injury, and very few cases of this have been reported. More often encountered (and still but a small chance) are elevated liver enzymes. Thusly, consistent level monitoring is recommended during initial introduction to observe and, if necessary, adjust dose, switch to another anti-androgen, or cease treatment in favor of estradiol monotherapy. Even if this does happen though, its not a major concern, similar to spironolactone’s risk of hyperkalemia! Regardless, I’d like to write a separate essay deep diving into that research.

I’m being quite vague about bicalutamide because of its newness. Having read dozens of studies on it, I feel comfortable enough to use it, but my expectations are tempered by the woeful limitations to available research. As it is primarily used in those with poor survivability outcomes, longitudinal studies are hard and prone to be poor quality without its use being expanded.

Conclusions

Both of these drugs have some level of quantified and unknown risk. They are also likely to be effective when used as part of a transfeminine hormone replacement therapy to produce the physiological outcomes desired. I can’t generally recommend one over the other for those looking to decide on what to initially start on based solely on pharmacological data.

It is notable that UpToDate, an often relied upon resource for doctors to make prescribing decisions, does not feature bicalutamide whatsoever in its trans health guidelines, or generally in its drug encyclopedia.³ Many prescribers don’t like to deviate from accepted standards, and if they cannot consult resources like UpToDate for a quick and comprehensive take, they may refuse you. Unfortunately, most doctors are overworked and don’t have the time to research things extensively themselves. If you find yourself in this situation, try to get a longer appointment and come prepared with sources and a terse, convincing argument.

I am not a doctor, and this essay is not meant to be a comprehensive assessment of these two drugs. When seeking HRT, your doctor will assess your health history and make the best choice available to them for suitable therapy. In some circumstances, they may not recommend you medically transition. Depending on the reason, it might be that bicalutamide could be a better fit. Having low blood pressure and thus not being able to take spironolactone is an example if you reject 5a-reductase inhibitors like finasteride on the basis of their efficacy as an anti-androgen.

Cost is often a major factor and spironolactone definitely beats out bicalutamide in this respect. For a month supply without insurance, the latter can be 5-10x as expensive. If you do have insurance, depending on its coverage, the gap could be less, or they may be the same price. 🤷 Check with your insurance, pharmacy discount programs and mail-order pharmacies before making a decision!

If you get side effects or aren’t meeting realistic transition goals while on spironolactone, maybe bicalutamide would be a better fit since it it isn’t a mineralcorticosteroid! It can’t hurt bringing it up to your doctor, and having a discussion about it. I myself was dramatically overprepared and had rather accommodating doctors, but this research may prove useful if you have to do some convincing for them to be comfortable prescribing it.

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