Anti-androgens Compared

Evidence Note

What is the question?

The anti-androgen’s job, alongside oestrogen, is to reduce androgen signalling — either by lowering testosterone production or by blocking its action at the androgen receptor — so the oestrogen can do its work. Four are in common use — spironolactone, cyproterone acetate, GnRH agonists and bicalutamide — and they act in different ways. This note is the short answer to how they compare, whether one is genuinely better, and how to think about the choice. It’s the distilled version of the full review, which grades each drug rather than ranking them. (It’s about adults on feminising hormones; puberty suppression in young people is a separate question, handled on its own.)

What does the evidence say?

There is no evidence-based overall “best” anti-androgen. The one time two of these drugs were compared head-to-head for a feminising outcome — cyproterone against spironolactone — cyproterone lowered testosterone considerably more, yet the two produced no measurable difference in breast growth over six months. The drug that “won” on the blood test showed no breast-development advantage in that trial. Beyond that single small study, the outcomes people care about — breast growth, body and facial hair, relief of dysphoria — are barely compared at all.

A testosterone level is a poor scorecard for some of these drugs. Two of them, spironolactone and bicalutamide, work mainly by blocking testosterone at the receptor rather than lowering the amount in your blood. So a still-detectable testosterone on spironolactone does not by itself mean the drug is failing — it can be working at a receptor the blood test cannot see. Bicalutamide takes this to the extreme: it blocks the receptor without suppressing testosterone, so the level can stay high despite the breast development that has been reported.

Each drug has its own main safety signal. Cyproterone is a reliable testosterone-suppressor, but carries a dose- and duration-related risk of a usually-benign tumour of the brain lining (meningioma) — expected to be lower at the low doses now standard, and it falls after stopping, though the exact low-dose risk isn’t well quantified. Spironolactone can raise potassium, especially with older age, kidney problems or other potassium-raising medicines. GnRH agonists sidestep the potassium, meningioma and liver signals of the other agents, but they’re expensive, given by injection or implant, and can cause an initial testosterone flare, and menopausal-type symptoms if oestrogen replacement is inadequate. Bicalutamide is convenient and mechanistically interesting, but the adult evidence is thin, and a rare, unpredictable liver injury is the main concern.

Oestrogen drives many of the feminising changes — but the anti-androgen still matters. The blocker reduces androgen signalling and can matter differently for different tissues; the oestrogen drives many of the changes and protects your bones. Whichever anti-androgen is chosen, having enough oestradiol matters more than which blocker you are on.

On skin and hair. Anti-androgens often improve androgen-driven oily skin and acne, and can thin and slow hair. But they do not remove established terminal facial hair — that needs electrolysis or laser, and an anti-androgen is not a substitute for it.

How strong is the evidence?

Split it in two. How each drug works, and what its main safety signal is, are on reasonably firm ground — decades of pharmacology, and for the risks, real cohort data. Which drug feminises best is not: there is a single small six-month trial comparing two of the four on one outcome, and nothing that ranks all of them across the outcomes that matter. The honest summary is that we understand these drugs’ mechanisms and risks better than we know which one works best.

Where are the uncertainties?

No properly powered trial ranks these drugs on the feminising outcomes people actually want. Bicalutamide’s benefits and safety in adults rest on thin, largely adolescent data. And the size of cyproterone’s meningioma risk at the low doses now used isn’t well pinned down. What all of this means is that the choice cannot honestly be made on “which is strongest” — because the evidence to answer that doesn’t exist.

There is no evidence-based “best” anti-androgen — only the one whose risks, benefits and practical demands fit the person taking it.

What does this mean for practice?

The choice is a safety-and-practicality decision, matched to you — your other conditions, the monitoring each drug needs, its cost and how it’s given, and your own priorities — not a league table of feminising power the evidence can’t supply. A few things follow. Judge a receptor-blocker like spironolactone by how you’re actually doing — with your clinician, and the monitoring that goes with it — not by whether a testosterone number has hit a target. Expect adequate oestradiol to matter more than which blocker you’re on. And don’t read “your testosterone is still detectable” as “the drug isn’t working” without knowing which drug it is. None of this is a reason to change anything on your own: which anti-androgen, at what dose, and how it’s monitored are decisions to make with your clinician.