Androgen blockers and progestogens

• 1: Androgen receptor blockers: Spironolactone and Bicalutamide
• 2: Inhibitors of 5a-reductase: Finasteride and Dutasteride
• 3: GnRH agonists and antagonists (“Puberty blockers”)
• 4: Synthetic progestogens (Androcur...)

1 - Androgen receptor blockers: Spironolactone and Bicalutamide

Androgen receptor blockers are molecules which have the capacity to bind to the androgen receptors. Remember the image of the key and keyhole? Androgen receptor blockers are like keys that fit in the keyhole, but can’t open it. And not only it can’t open it, but it’s stuck in there so that the keys that could actually open it can no longer get in. So, a bit like when your key breaks in the lock before you open the door…

What this also means is that what is blocked is the reception of androgens (and hence their effects), but not the production.This doesn’t make them less effective. If your levels of estrogens are not blocking the production of testosterone (which would be the reason you want to take androgen blockers), then testosterone will still run in your system, and you will still see it on the blood test results. This doesn’t mean the treatment doesn’t work, and you should judge this by the results you feel and observe on body changes.

The main drugs in the category are Spironolactone and Bicalutamide. Flutamide is a sort of earlier and much more risky version of bicalutamide, and it has been removed from the market in many countries.

😐 Spironolactone

This is actually a diuretic medication in the first place (i.e. intended to make you pee). Its anti-androgenic function is one of its secondary effects. In addition to working as a receptor blocker, it also has a small 5a-reductase inhibition power (prevents conversion of Testosterone into its more potent form DHT - read more in the dedicated section).

One issue is that it also blocks other receptors, mainly the ones of progesterone, and cortisol, which can lead to undesired effects.

The main issue reported by transfem people using it is its diuretic effect.

It also comes with risks of hyperkalemia, which is an excess of potassium. This can have dangerous consequences on cardiac health. For this reason, you might want to monitor your diet, keeping an eye on your potassium and sodium intake.

Finally, many report poor efficacy as an androgen blockers. All of the above gives a pretty bad reputation to spironolactone in the trans community, but it remains a widely prescribed drug in feminizing HRT - especially in the USA.

Pros

• Convenient and usually cheap

Cons

• Limited efficacy
• Makes you pee
• You might need to monitor your diet to avoid potassium excess

✅ Bicalutamide

As opposed to spironolactone, bicalutamide has been conceived as a pure androgen blocker in the first place, in order to treat prostate cancer, and later on hirsutism, and as a puberty blocker. It blocks the reception of androgens in a very efficient way, without blocking other receptors, hence limiting the secondary effects. It is increasingly considered one of the best alternatives among androgen blockers, along with GnRHa.

A study showed that it has feminizing effects by itself, as the testosterone running in the body without finding a place to bind is eventually aromatized into estradiol, giving higher estradiol levels than when testosterone finds and binds to its receptors. However, it is safer to never take an androgen blocker by itself, and always add estrogens.

Pros

• Very efficient
• Nearly no secondary effects and low risks for health

Cons

• Sometime a bit expensive
• Practitioners are a bit reluctant to prescribe (because uniformed)
• You have to monitor your liver health (though the risks remains considerably lower than with synthetic progestins like Androcur)

Dosage

A dosage of 50mg/day is usually sufficient. If your testosterone has already been lowered with negative feedback, half this dose can be enough to block the leftovers of testosterone (take one 50mg pill every other day). If you feel masculinising effects coming back, return to 50mg/day. Theoretically, 50mg of bicalutamide can block around 200 ng/dl of testosterone (1mg of bica blocks 4ng/dl).

Keep in mind that it will not affect the levels of testosterone shown in the blood test results. This is absolutely normal.

More resource on bicalutamide

General information articles on bicalutamide :

• Bicalutamide – Wikipedia
• Medical uses of bicalutamide – Wikipedia
• Side effects of bicalutamide – Wikipedia
• Pharmacology of bicalutamide – Wikipedia
• Comparison of bicalutamide with other antiandrogens – Wikipedia
• FAQ par transfemscience.org

Specific sections with information on bicalutamide (and other nonsteroidal antiandrogens) in transgender women :

• Medical uses of bicalutamide § Transgender hormone therapy – Wikipedia
• Transgender hormone therapy (male-to-female) § Nonsteroidal antiandrogens – Wikipedia
• Flutamide § Transgender hormone therapy – Wikipedia
• Nilutamide § Transgender hormone therapy – Wikipedia
• Specific sections with information on bicalutamide (and other nonsteroidal antiandrogens) in cisgender women :
• Medical uses of bicalutamide § Skin and hair conditions – Wikipedia
• Bicalutamide § Research – Wikipedia
• Flutamide § Skin and hair conditions – Wikipedia
• Nilutamide § Skin and hair conditions – Wikipedia

Specific sections with information on bicalutamide in boys with precocious puberty (potentially relevant to the use of bicalutamide as a puberty blocker in adolescent transgender girls) :

• Medical uses of bicalutamide § Male early puberty – Wikipedia

Scientific Literature

• Relevant literature excerpts on bicalutamide in transgender women
• Care of Transsexual Persons (Gooren, 2011)
• Bicalutamide as an Androgen Blocker with Secondary Effect of Promoting Feminization in Male to Female (MTF) Transgender Adolescents (Neyman, Fuqua, & Augster, 2017)
• Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents (Neyman, Fuqua, & Eugster, 2019)

Literature reviews on bicalutamide (and other nonsteroidal antiandrogens)

• Bicalutamide § Further reading – Wikipedia
• Bicalutamide / Nonsteroidal Antiandrogens – PubMed (filter search results by « Review » in the left-hand column)

Regulatory Body Materials

• Casodex (bicalutamide) 50 mg FDA (US) label
• Casodex (bicalutamide) 150 mg MHRA (UK) prescribing information
• Casodex (bicalutamide) 150 mg MHRA (UK) patient leaflet (PDF)
• Casodex (bicalutamide) 50 and 150 mg MHRA (UK) public assessment report

Reddit

• Bicalutamide (Casodex) as an Antiandrogen for Transgender Women Megathread
• Bicalutamide frequently asked questions (FAQ) and common misperceptions
• Scientific Literature about Bicalutamide
• Hormone Therapy for Transgender Women 101 – u/Alyw234237
• Recent Study: Bicalutamide in MtF Adolescents (value as an AA and for promoting feminisation) – u/Ambrosia25
• Calculation and discussion of bicalutamide dosage potentially required for puberty blocking in MtF trans girls – u/Ambrosia25 (direct link to the document/email being discussed here)
• Rise in blood levels of bicalutamide for various dosages (graph) – u/Ambrosia25
• Indirect evidence that bicalutamide is able to provide the same benefits as flutamide for scalp hair loss – u/Ambrosia25
• A ranking of AAs in terms of Safety, Effectiveness, Tolerability and Cost (inexpensiveness) – u/Ambrosia25
• New publication: Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents (Neyman, Fuqua, & Eugster, 2019) – u/Alyw234237
• Hormone Therapy for Transfeminine Non-Binary Individuals and Femboys 101 – u/Alyw234237

News and Blogosphere

• Bicalutamide, a new anti-androgen for trans women and girls (Jones, 2018)

⛔ Flutamide

It is considered an “ancestor” of bicalutamide. It works the same way, but with much more risks and side effects, especially on liver function. It should NOT be prescribed by any practitioner, and has been put off market in many countries.

2 - Inhibitors of 5a-reductase: Finasteride and Dutasteride

5a-reductase (5 alpha) is an enzyme responsible for the conversion of testosterone into its much more potent form DHT (dihydrotestosterone). The particularity and mode of actions of this group of medication is to inhibit the production of this enzyme, and hence blocking the conversion of T into DHT. DHT is considered to have masculinizing effects up to 10 times stronger than testosterone, and it is the main hormone responsible for hair loss (sometimes called “male pattern hair loss”). This is why the medications of this group (Finasteride and Dutasteride), are most commonly prescribed to cis-men seeking to reduce hair loss.

One problem is that the enzyme 5a-reductase is responsible for at least 9 other conversion reactions in the synthesis of steroid hormones. Consequently, inhibiting it does not only affect the conversion of testosterone to DHT.

An other problem is the medication won’t affect the levels of testosterone (the portion of T that would have been converted into DHT will remains as… testosterone), which will still run in the bloodstream, reach its receptors unhindered, and lead to masculinizing effects. This is why these medications will in no way be enough to block androgenic activity, and allow for feminization. It is only useful to reduce hair loss, and the best remains to consider another option to actually block the effects of testosterone (production or reception). Besides, low testosterone also means low DHT, since there is no testosterone to convert! This is how absurd the prescription of these medications is.

By opting for another blocker, you will find two benefits: Actually achieve better feminization, since with 5a inhibitors alone, your testosterone levels will remain unchanged. Avoid the negative side effects of the 5a inhibitors. These mostly come from the fact the 5a-reductase is also responsible for many other hormones synthesis, whose perturbation can cause anxiety, depression, suicidal ideation, neurological diseases and loss of libido.

The only reason to consider finasteride/dutasteride is if you managed to significantly reduce your testosterone by another way, but you still seem to be affected by hair loss, and you show abnormaly high levels of DHT on the blod tests. And considering the side effects, this decision should not be taken lightly.

Finasteride

Conceived for cis-men preoccupations: to reduce the levels of DHT (and hair loss associated) while keeping high levels of testosterone.

If you do not have abnormally high levels of DHT despite reducing your testosterone, taking finasteride is only taking unnecessary risks, without any benefits!

Finasteride is at the origin of the healthcare scandal called “Post-Finasteride Syndrome”. This “syndrome” is a set of effects such as anxiety, depression, suicidal ideation, neurological diseases and loss of libido. If this syndrome strikes a minority of finasteride users, they can be permanent, and persists after stopping the treatment.

Dutasteride

All what we said of finasteride is true of Dutasteride. The only difference is that dutasteride is able to prevent even more efficiently the conversion of testosterone into DHT.

3 - GnRH agonists and antagonists (“Puberty blockers”)

Agonists and antagonists of GnRH (Gonadotropin Releasing Hormones) are mostly known by most people as the “puberty blockers” proposed in some countries to minors, before adding exogenous sex hormones. But blocking puberty means nothing else than to block the production of endogenous sex hormones. Consequently, GnRHa can be used as a very efficient androgen blocker for all transfem people (as well as transmasc people)

They have mostly been conceived to treat hormone-dependent cancers (breast, prostate), but also as puberty blockers for cisgender children who show signs of puberty at an age considered too early. In this respect, it is good to notice that the medication has been given to cisgender children without any protest and concerns, but it has become a public health debate at the moment it was used for trans children/teens.

In practice, they work by blocking the production of testosterone at the very early stage of the process. We make the distinction between GnRH antagonists and GnRH agonists. Both work at the same level of the production chain, but in opposite ways; but both reach the same goal, and have the same effect - nearly total shutdown of testosterone production.

Sex hormone production is controlled by the levels of FSH and LH. The production of these is itself controlled by pulsatile release of GnRH. The idea of the medication is to reduce the levels of FSH/LH and hence of testosterone; this is where the distinction between antagonists and agonists is important.

• GnRH antagonists will reduce FSH/LH by blocking the reception of GnRH by the pituitary gland, which then doesn’t get the order to produce FSH/LH. They work on the pituitary gland’s GnRH receptors the same way bicalutamide works on the body’s androgen receptors: the broken key in the lock, which can’t be opened anymore. A GnRH antagonist available in Sweden is Degarelix (Firmagon), but is nearly exclusively prescribed for cancer treatment.

• GnRH agonists work by over stimulating the pituitary gland, which, after a phase of high production of FSH/LH (and hence a peak of testosterone of about a week), will stop reacting to GnRH, and hence the whole sex hormone production will shut down. Common GnRH agonists (the most commonly prescribed because cheaper) are Triptolenin (Gonapeptyl) and Leuprorelin (Eligard, Enanton, Procren). Usual doses of 3mg/month or 11.5mg/ 3 months.

A peak of testosterone will start around the 3rd day after the first injection. It will last around a week and does not repeat afterward on the next injections. Some people use bicalutamide in order to counter the effects of testosterone during this peak phase.

They are all quite safe, with nearly no side effects, and great efficacy. Their main problem is that they are usually quite expensive, making them difficult to access if you don’t have health insurance, or just hard to get prescribed because practitioners will tend to favor cheaper alternatives. Besides, they mostly in the form of injections, given every month or every 3 months.

A nasal spray exists (Nafarelin, sold under the brand name Synarel) which can be a good alternative for people who prefer to avoid injections.

4 - Synthetic progestogens (Androcur...)

Progestogens is the third group of sex hormones after androgen and estrogens. We will differentiate here between “natural” (bioidentical) progestogens (progesterone is the main one) and synthetic progestogens, developed by the pharmaceutical industry for different purposes (namely contraceptive medications, and anti-androgen medications).

Progestogens’ main function, for ciswomen and AFAB people, has to do with ensuring the means and continuation of pregnancy: regulate the cycle, maintain the endometrial tissue of the uterus during and after ovulation, allow lactation…

For transfem people, only the secondary effects of progestogens are of interest. Those effects includes:

• Reduces the production of testosterone (anti-androgen)
• May help finalize breast growth by developing terminal lobules necessary for lactation.
• May terminate/limit breast development if taken before Tanner stage 3.
• Can cause the chest to swell.
• May alter water retention by the body.
• May increase appetite.
• May promote fat accumulation and weight gain.
• May increase metabolism.
• May promote sleep.
• Can increase or on the contrary decrease the libido.
• Can limit or on the contrary aggravate hairiness
• May cause drowsiness and dizziness (only for progesterone).
• May increase the sensation of dysphoria.
• May increase the risk of depression.
• Increases the risk of breast cancer (particularly for synthetic progestins).

Most of the negative effects given above are associated with synthetic progestogens.

Synthetic progestogen:

So, why would you take synthetic progestogens? Because they can work as very efficient anti-androgen, thanks to the natural negative feedback: more of any sex hormones leads to less of endogenous sex hormones. To the body, a synthetic progestogen is read as any other sex hormones: enough of it will start the negative feedback mechanism.

This is true of bioidentical progesterone and synthetic progestogens. The difference being that bioidentical progesterone has a weak effect of negative feedback (you would need a lot to start it), when synthetic progestogens have been developed in order to have a very strong effect as they last much longer in the body.

Androcur

The most potent and widely prescribed synthetic progestogen is Cyproterone Acetate, sold under the name of Androcur. The use of Androcur is banned in the US because of its risks of liver failure, in favor of Spironolactone. In the UK, GnRHa are largely prefered. Androcur remains the most prescribed anti-androgen medication in Europe.

Androcur accumulates the strong anti-androgenic effect through negative feedback, with a small androgen receptor antagonist, plus all progesteronic effects - especially those of synthetic progestogens. It carries a load of adverse side effects, namely prolactinemia (possibly leading to bone problems) and meningiomas (tumor of the meninges). In some countries, like France, a doctor cannot prescribe Androcur without written consent of the patient, and regular MRI scans.

It is also associated with liver failure, and depression.

If you cannot access another medication, you should try to limit the doses as much as possible. Studies have shown that Androcur reaches its maximal effect at 10mg/day. It is unnecessary to exceed this dose, and that would only expose you to more risks.

Pros:

• Very efficient anti-androgen
• Stronger progesteronic action than bioidentical progesterone

Cons:

• Important risks of depression
• Associated with drastic fall of libido
• Risks of prolactinemia, liver failure, meningiomas
• Might perturb breast growth if taken before Tanner stage 3

Androcur is one among many synthetic progestogens. All the others have their bunch of undesired side effects, mostly - at different degrees - depression, liver failure, and prolactinemia. Those drugs include Levonorgestrel, Dydrogesterone, MPA, Norethisterone…