Most people undergoing feminising hormone therapy will be taking an “anti-androgen” along with an oestrogen and possibly progesterone. The anti-androgen is a critical part of the hormone therapy as androgens block feminisation more than oestrogens promote it, so without an anti-androgen very little if any change would occur.

However there are several different medications used any they all work differently, so lets dig in to this and see how they actually reduce androgen levels. I’ll look at the three most commonly used in New Zealand - cyproterone acetate, spironolactone, and goserelin/Zolodex - and I’ll also add bicalutamide, progesteone and estrogen mono-therapy.

Cyproterone Acetate

Cyproterone acetate, commonly referred to as cypro or CPA, is generally the first choice of anti-androgen in New Zealand. CPA is a synthetic progestin with anti-androgenic and anti-gonadotropic effects¹, though at the doses between 12.5mg every other day and 25mg daily typically given for gender-affirming hormone therapy (GAHT) the anti-androgenic effects are not significant and the anti-gonadotropic effects dominate².

That’s a lot of medical terms, time to break them down.

Synthetic Progestin

Cyproterone is a synthetic hormone that can stimulate the progesterone receptors in the body while not being progesterone, these are collectively referred to as progestins¹. These are generally used by bypass the body’s normal safeguards against external hormones, as the liver is extremely good at filtering them out.

Synthetic progestins stimulate progesterone receptors just like normal progesterone, though some may bind for longer or stimulate more than progesterone would. They also lack the metabolites of progesterone, which can be both good and bad and are a whole post to themselves.

Cyproterone is a very potent progestin, with studies showing it’s about twice as likely to bind to a progesterone receptor as progesterone itself. This coupled with the near 100% bio-availability means it very strongly activates progesterone receptors³.

Anti-androgen

While we talk about all these medicines as anti-androgens there are several different mechanisms to achieve that, but the one that’s most commonly meant by the term anti-androgen alone is an androgen receptor antagonist - that is a substance that prevents androgens binding to the androgen receptors and triggering their effects⁴.

In high doses of 50-100mg/day cyproterone is an anti-androgen, but below that it has no significant anti-androgenic effect⁵.

Cyproterone isn’t a pure androgen receptor antagonist though - it’s a very weak partial agonist. This means it doesn’t just block the androgen receptor, it does stimulate it a bit. However this stimulation is a much lower level than testosterone. This is unlikely to matter outside of treatment of androgen-dependant cancers.⁵.

Anti-gonadotropin

This is actually an effect of cyproterone being a progestin. It blocks release of luteinizing hormone and follicle-stimulating hormone which are the hormones that stimulate the gonads to produce sex hormones². These effects are significant at doses of 5-10mg/day⁶, so while this level of cyproterone won’t block testosterone receptors instead it stops the production of testosterone in the first place.

Side effects

Cyproterone has several known side effects. It reduces serum B12 levels⁷, which for most people is inconsequential but some may need supplements if symptoms of B12 deficiency such as depression and anxiety occur. Cyproterone also has the same side-effects as synthetic progestins - an increased risk of blood clots, breast cancer, meningiomas (benign brain tumours, not cancerous), and increased prolactin levels. In high doses it is also toxic to the liver, especially in those with pre-existing liver damage⁷.

Most of these side effects are dose-dependant, with doses under 10mg per day not having significant effects, so low-dose cyproterone acetate is regarded as safe.

However doses of over 50mg per day significantly increase risks, with doses of 100mg daily showing a 400-fold increase in the risk of brain tumours for an absolute incidence of 15% of those treated, a 4-fold increase in the risk of blood clots, and 4.5x increase in the risk of breast cancer⁸.

Summary

Cyproterone lowers testosterone levels by blocking the hormone signalling pathway that manages testosterone production. It’s also a progestin so will have many of the effects that progesterone would have, but it won’t have any of the benefits of progesterone metabolites.

Spironolactone

Spironolactone, often known as spiro, seems to be one of the most common anti-androgens prescribed worldwide and it’s commonly used here as well. Spironolactone is a strong antimineralocorticoid, a moderate antiandrogen, and a weak steroidogenesis inhibitor⁹.

Yay more words!

Antimineralocorticoid

Mineralocorticoids are hormones that regulate the minerals in your blood, specifically sodium and potassium. Mineralocorticoids cause potassium to be excreted via the kidneys and sodium to be retained, and unsurprisingly antimineralocorticoids cause the opposite. Now if your kidneys are excreting more sodium than they would usually they’ll need to use more water to do this, and consequently fill your bladder faster. That’s why spironolactone is a diuretic¹⁰.

Moderate antiandrogen

Spironolactone’s anti-androgenic effect is similar to cyproterone acetate - it’s a weak partial agonist so it blocks the receptor, stimulates it a little, but then stays so testosterone can’t bind for a while. The stimulation of the testosterone receptors is not significant for gender affirming therapy, but can be in other areas.¹¹.

Spironolactone only has a slightly higher affinity for the androgen receptor than cyproterone acetate¹¹, but it can be safely taken in much higher doses so the anti-androgenic effect is the predominant one.

Steroidogenesis inhibitor

Like cyproterone, spironolactone also inhibits the production of testosterone directly. However unlike cyproterone this is not a the main effect of spironolactone as it’s a pretty weak effect. Spironolactone inhibits the activity of key enzymes in testosterone production, but the dose to make this significant is extremely high⁹.

Side effects

Spironolactone has very few side effects, though the most common ones are fatigue and related symptoms¹⁰. The most serious effect is increased blood potassium levels which can result in hyperkalemia, which if left unchecked can be fatal. However this is only a serious risk in people with impaired kidney function or using low-sodium salt as part of a low-sodium diet¹⁰. Kidney function checks should be part of regular blood tests while on spironolactone.

The other noticeable effect is reduced blood pressure, which is one of the main uses of spironolactone in medicine.

Summary

Spironolactone functions mostly as an androgen receptor blocker, though it also very weakly stimulates the receptor. It also has minor effect inhibiting testosterone production, but this is very weak.

It’s pretty safe, but it is a diuretic.

Goserelin

Goserelin, the brand name Zolodex is used in NZ, is a GnRH agonist. It’s supplied as a subcutaneous implant that lasts either one or three months and has almost no side-effects that aren’t due to low hormone levels.

GnRH?

GnRH is short for Gonadotropin Releasing Hormone. It’s a hormone that forms part of the signalling pathway that causes sex hormones to be produced, specifically it triggers the release of luteinizing hormone and follicle-stimulating hormone¹² (remember those?).

Normally gonadotropin releasing hormone is secreted in pulses by the hypothalamus, the frequency and length of the pulses determines the hormone production¹². And for the nerds out there you’ll recognise this as pulse-width modulation. Isn’t it neat how biology was millennia ahead of us?

Agonist?

Cyproterone and Spironolactone are both functionally antagonists - they block the effects by binding to but not stimulating a hormone receptor.

Goserelin is a GnRH receptor agonist, it stimulates it. Which sounds odd, wouldn’t this cause more lutenizing and follicle-stimulating hormone to be released, and therefore increase hormone production, the thing we’re trying to stop?

Yes, it absolutely does.

However normally GnRH comes in pulses. Goserelin is contained in an implant that constantly releases it so the GnRH receptors are constantly stimulated. This results in receptors essentially shutting down; they’re getting a bad signal so they switch off. This then stops all the hormone productions signalling and the production of sex hormones¹².

This is also why cyproterone acetate is frequently prescribed for the first week of goserelin use - it block the production of lutenizing and follicle-stimulating hormones and blunts the initial surge of hormone production¹³.

Side effects

GnRH agonists in general have very few side effects that aren’t simply a consequence of stopping hormone production¹². They are one of the safest and most well understood medications used for suppression of sex hormones because they selectively target a single signalling pathway.

Summary

Goserelin interrupts the signalling that would normally cause testosterone production by overloading it, this stops your body producing testosterone. As a very selective medicine it has very few side effects.

Bicalutamide

A mention because it comes up often in reports from the USA. Bicalutamide is available in NZ, but isn’t normally prescribed for gender affirming therapy.

Bicalutamide is almost purely a silent androgen receptor antagonist¹⁴. This is different from both cyproterone and spironolactone which are technically weak androgen receptor agonists - they block the receptor and provide a very low level of stimulation - and also bind to other receptors in the body.

Additionally bicalutamide does not bind to any other receptors or suppress the normal hormone regulation pathways. This makes it interesting as while it does not suppress testosterone production at all it effectively blocks its action in most of the body¹⁴. Unfortunately this means that measuring blood testosterone level is not a useful way to test its efficacy¹⁵.

Side effects

As bicalutamide has a very strong selectivity for the androgen receptor it has very few side effects that aren’t simply a result of blocking androgens¹⁴, however like cyproterone acetate there are rare cases of liver toxicity that show up early in treatment¹⁵.

Summary

Bicalutamide is a selective androgen receptor antagonist. It has a very rare chance of liver toxicity, but as it is highly selective for the androgen receptor it does not have any other side effects. However it will not lower blood testosterone levels so this cannot be used to measure its efficacy.

Atypical anti-androgens

There are other ways to suppress testosterone that aren’t commonly thought of that way, but that have been shown to work. I’ll briefly cover those.

Progesterone

Remember how Cyproterone Acetate gets most of its effect at gender-affirming doses from its progestrogenic effects? That means progesterone itself will work just as well for suppressing testosterone!

Why don’t we use it? It’s down to bioavailability and metabolism. Oral progesterone has a bioavailability of around 2.4%¹⁶, which means a 100mg oral capsule results in 2.4mg getting in to circulation. To match the lowest effective does of cypro, 5mg⁶, coupled with cypro having twice the affinity of progesterone itself for the progesterone receptor³ would require 500+mg of progesterone daily.

Estradiol

Estradiol itself is an anti-androgen by its function in the signalling pathway that controls sex hormone production. The GnRH releasing neurones sense hormone concentrations in the blood, and elevated estrogen levels cause them to lower hormone production. However this is a complex process that depends on several other hormones¹⁷, which means it’s hard to calculate a dose of estradiol which would suppress testosterone sufficiently.

References

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