Mar 282016

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.

The chemical structure of cyproterone

The chemical structure of cyproterone

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.

May 012013

One way to reduce stress and cortisol - CC BY 2.0 - flickr user eamoncurry123Summary: Research now indicates that cross-sex hormone therapy is associated with a lower cortisol awakening response in trans people, regardless of attachment style. Many confounding variables, however, were present in this study.

Transgender people have long asserted that gender dysphoria can be extremely distressing and that transition, including hormone therapy, helps relieve that dysphoria. Hormone therapy is known to improve self-reported quality of life, as measured by questionnaire. To my knowledge no other study has looked at stress-related biological factors in trans people. Biological factors are important because self-report is notorious for validity problems. This study looked at one such biological factor, called the cortisol awakening response.

What is the cortisol awakening response? Readers of the blog may remember the last time I spoke about cortisol (paragraph #2). For those who don’t remember…. cortisol is a “stress hormone.” When we’re stressed, whether by speaking in public or running from a lion, cortisol is released. It helps our body be ready for immediate survival by increasing blood sugar and helping with metabolism. High cortisol levels over a long period of time can have many negative effects on health, including weakening the immune system. The cortisol awakening response is part of the daily cycle, when blood levels spike about 20-30 minutes after waking in the morning. The cortisol awakening response is larger in stressed people than in non-stressed people and can be affected by many things, including burn out, fatigue, aspirin, and sleep schedule. Awakening response is thought to be a good indicator of general stress levels and as a good indicator for stress-related disease risks. In case you start suffering from insomnia take a look at the best CBD oil for sleep with no side effects that can reduce the risking your health.

Participants in this study were 70 trans people seen at the Gender Identity Unit of the University of Bari Psychiatric Department, roughly 64% trans women. All the participants had the same hormonal treatment; transdermal estradiol gel and cyproterone acetate (an anti-androgen) for trans women, intramuscular testosterone esters for trans men. They were assessed before hormone therapy and 12 months after starting hormone therapy. There was no significant difference in age, education, or occupation between the two groups.

The researchers measured perceived stress (a self-report of how stressed a person feels) in addition to the cortisol awakening response. The cortisol awakening response was measured by a blood test at 8:00am on three consecutive days, 1 hour after waking.

The results were striking. Before treatment, both perceived stress and cortisol levels were above the  “normal” range. After twelve months of hormone therapy, both were much lower and back within normal ranges. There were no statistically significant differences between trans men and trans women.

However there are a number of confounds for this study. Cortisol levels vary with sex hormones. For example, the cortisol levels of menstrual women will vary depending on which part of the menstrual cycle they’re in. Could cross-sex hormone therapy have caused this change in cortisol levels? Maybe, but then I’d expect there to be a difference between the trans men and trans women in this study and there weren’t.

The researchers also did not appear to attempt to control for other factors which could have impacted the cortisol awakening response. Changes in sleep patterns (e.g., naps) or sleep quality (e.g., a noisy environment) have effects on the cortisol awakening response. As far as I can tell the researchers did not screen for these changes.

Cortisol and stress were not the only things measured in this study. The researchers also looked at attachment styles. Attachment styles are a psychological concept. The idea is that when we are children our interactions with parents, and how they respond to our needs, affects the type of “attachment” we have. Attachment styles are secure or insecure. A secure attachment often results in happy adult relationships. Insecure attachments include avoidant, anxious, and unresolved/disorganized styles. Attachment styles may influence how we respond to stress, so they could have been a confound in this study if not examined.

The researchers determined the attachment style of the participants with a structured interview. They found that trans people are more likely to have an insecure attachment (70%) than the general population with no psychiatric diagnoses (44%). Attachment style did not, however, appear to be correlated with cortisol awakening response or perceived stress.

In other words, the relationship trans people have with their parents did not appear to affect the stress-reducing effects of hormone therapy.

I do not really understand why these researchers chose to examine attachment style in this study. I think that knowing attachment styles may be useful for therapy or for the development of effective variations on therapies for trans people. But I don’t feel that the inclusion of attachment style was sufficiently justified in this study. Why look at attachment and not, for example, socioeconomic status or social support? I would think either of those would be more likely to have an impact on stress levels than attachment.

On the whole: I think that the cortisol results of this study are decent validation of the anecdotal evidence from trans people themselves, but that the exploration of attachment style in this context is a red herring.

The abstract is publicly available.