In the United States, spironolactone is the oral anti-androgen of choice for trans women. It’s the cheapest and is well tolerated by most people. Outside of the United States cyproterone acetate, also known as Androcur, is the preferred drug. This week I take a look at this drug, how it works, and why it hasn’t been approved for use in the United States.

Cyproterone is an anti-androgen. It blocks androgen receptors, preventing testosterone and other androgens from having their effects. By blocking those receptors, it reduces the amount of testosterone in the body through a mechanism called negative feedback. Cyproterone is chemically similar to progesterone and has some progesterone-like effects as well. Outside of transgender care it’s also used for prostate cancer, as combination antiandrogen and hormonal birth control for cis women (e.g., Dianette), and for chemical castration of sex offenders.

It’s available both as a pill and intramuscular injection. The pill form should be taken every day at the same time after a meal. The dose often used for transition in the literature is 100mg/day. Anecdotally I’ve been told that lower doses, such as 25-50mg/day, have been used. The injection is given once every 1-2 weeks.

Cyproterone acetate is not risk-free and is definitely not for everyone. Most seriously, cyproterone is associated with liver damage. That damage can be severe. It can lead to liver failure even after the drug is stopped. Damage has been reported with doses over 100mg/day. Because of this, people on cyproterone should have their livers regularly monitored with blood tests. The drug should not be combined with other drugs that can cause liver damage. That includes alcohol and many prescription drugs. Individuals with known liver damage/disease should not take cyproterone.

There is also some question of whether the drug is associated with some cancers. In particular, liver cancer and some brain cancers. Specifically, hepatocellular carcinoma and meningioma are the cancers of concern. Researchers are still exploring this connection. Other negative side effects of cyproterone include allergic reactions and worsening of depression.

Many trans women are concerned about fertility. The effects of cyproterone alone, without estrogen, on fertility are somewhat known. Sperm count goes down with oral doses as low as 50mg. Infertility can happen in as little as 2 months. The infertility is reversible once cyproterone is stopped. Fertility returns anywhere from 3-20 months. But remember — no anti-androgen is a birth control method. Please use birth control if you or your partner are at risk of pregnancy.

In the literature, 100mg/day is the dose that seems to be preferred for transition. No cases of liver cancer in trans women have been reported. However some women do have higher levels of liver enzymes. That’s a sign that the drug is causing some damage to liver cells. Transdermal, instead of oral, estrogen is recommended to reduce potential liver damage and blood clots.

Cyproterone is a potential alternative for trans women. So why hasn’t the FDA approved it? That’s a little murky. I wasn’t able to find public document describing the reasoning. But the biggest reason cited by other sources is the concern of liver damage. The FDA is likely trying to do its job and protect the population from drugs that cause more harm than good. In its efforts it may well overstretch. Cyproterone only rarely causes liver problems, and those problems can be screened for with regular blood tests. However it’s important to remember that there are safer alternatives still available. Spironolactone and the GnRH agonists (puberty blockers) are generally safer and mostly well tolerated. Other androgen receptor blockers (e.g., bicalutamide), while not in common use for trans care, are also available and have lower rates of liver damage. So there’s little pressure on the FDA to approve a riskier drug.

So in summary — cyproterone is an androgen receptor blocker in use outside the United States for trans care, prostate cancer, and birth control. It’s biggest side effect is potential liver damage. It’s not FDA-approved for use in the US probably because of that liver damage. People currently using the drug should be under a physician’s supervision.

Want to learn more? The wikipedia article on this drug is super excellent!

Note on references — I pulled most of my information from LexiComp, which I have access to through my university and can’t easily reference. However, prescribing information is publicly available and has much of the same information.

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