Feminizing HRT

• 1: The different methods
• 2: SHBG: What is it, and why it can matter
• 3: Estrogens
• 3.1: Transdermal gel and patches
• 3.2: Oral
• 3.3: Injections
• 3.4: Pellets
• 3.5: Sources on the risks of thrombosis
• 4: Androgen blockers and progestogens
• 4.1: Androgen receptor blockers: Spironolactone and Bicalutamide
• 4.2: Inhibitors of 5a-reductase: Finasteride and Dutasteride
• 4.3: GnRH agonists and antagonists (“Puberty blockers”)
• 4.4: Synthetic progestogens (Androcur...)
• 5: Progesterone
• 6: Maintaining erections and healthy penile tissue: topical testosterone
• 7: That was a lot... So, what should I take?

1 - The different methods

There are different “methods” in feminizing HRT, or medication regimes, whith each their pros and cons. Here are the main ones.

Monotherapy

As we have described in the “Basic science” section, monotherapy consists in using only exogenous estradiol to reduce the levels of testosterone to target levels, thanks to the negative feedback mechanism.

In other words, you take enough estradiol which does the two things you want: reduce your testosterone, increase your estradiol. Simple enough. Where’s the catch? There is not really any.

Pros:

• Very easy to put in place - take enough estradiol until testosterone crashes down.
• Avoid taking androgen blockers with their lot of side effects
• Higher doses of estradiol usually means better mental health and libido.
• If you are paying for your medication - it can be a cheap option. Both gel and injections are usually cheap.

Cons:

• You have to make sure that you keep your estradiol levels high enough. The threshold to activate the negative feedback is different for each person, but is usually situated around 200 pg/ml.
• Not compatible with all routes of administration, especially oral and patches. Injections are ideal but unavailable through the regular market in many countries, including Sweden. Possible with gel depending on skin receptivity, and using higher doses and/or scrotal method.

Estradiol + progesterone

This could be considered a variation of monotherapy, since the main principle remains the same: using estrogens to naturally reduce testosterone through negative feedback. Adding progesterone can act as a minor complement in case estrogens themselves are not high enough to start negative feedback.

The use of progesterone for feminization, however, is still debated, and its role remains unclear. There are a few things to know in case you decide to take it:

• As we said, it has a small anti-androgen power for AMAB (by negative feedback), but you should not count on it as the only way to efficiently bring down your T. It can be interesting in combination with a relatively high dose of estradiol - as a complement to monotherapy.
• Its role on breast growth is still unclear. Some say it helps from the beginning, but much research suggests it can also limit or block breast growth if taken too soon. The main recommendation is to start after reaching stage 3 of Tanner scale (approx. 2 years of HRT).
• Using oral route (swallowing) results in no effects whatsoever, since the liver first pass will convert and eliminate nearly all of the progesterone. The new converted molecule can cause somnolence and other mood effects, which are actually appreciated by some people. So if you want those effects, you can eat the pill, but it will have, for sure, no effects on breast development and/or testosterone blocking. Otherwise, the best way to reach useful levels is rectal administration, if you get those soft pills. Put one (100mg to 200mg) up your butt before going to sleep.
• In any case, always use bioidentical progesterone, and not synthetic progestogens.

Estradiol + blockers

This consists in using an androgen blocker (blocking either production or reception), in complement to estrogens. There are many androgen blockers, each with different effects and risks. We’ll come back in the next section to all of them in detail. Cyproterone acetate (sold under the name Androcur in many countries) is one of them, even though technically, it is a synthetic progestogen, meaning that its action relies on negative feedback, like monotherapy. Unlike bioidentical progesterone, its antiandrogenic power is extremely strong. However, it doesn’t make it a safe blocker since, unlike bioidentical progesterone, it comes with a bunch of frequent and significant health risks that are common to synthetic progestogens.

Pros:

• You can independently adjust your levels of T and E. (Does not apply to receptor blockers)
• It is the only way to block testosterone if monotherapy doesn’t work for you (insensitivity to gel, or you can’t take high dosage of estrogens…).

Cons:

• You have to make sure that your are not underdosed in estrogens, since being deficient in both sex hormones at the same time can be dangerous (physically and mentally - mainly risks of osteoporosis and depression) NOTE THAT ANDROGEN BLOCKER SHOULD NEVER BE TAKEN ALONE.
• Lots of androgen blockers are known to have annoying if not dangerous side effects. It is the case of Androcur, widely used in Europe.

Dr. Will Power’s method

The main difference is that Power’s research and experience seem to show that putting estrone (E1) into the equation is important. His idea is to start with higher estrone levels for around 6 months by using oral estradiol pills. As we’ve said before, if simply swallowed, most of the estradiol of these pills is converted to estrone. Power claims that this is closer to the hormonal balance evolution in ciswomen puberty, and that initial exposure to estrone helps increase the amount of estrogen receptors. The idea is to prepare the ground for estradiol, which comes after the first 6 months, by maximizing the reception capacities. Introduction of estradiol (E2) after the 6 months of dominantly estrone therapy is realized at high, monotherapy-like dosage (usually injections, sometimes gel). As we said, blockers are sometimes used to complement, as well as progesterone after reaching Tanner stage 3 (around 2 years of HRT).

This initial estrone treatment is what differentiates his method, and also what makes it controversial among healthcare practitioners and the trans community. Indeed, estrone exposure is associated with higher and more frequent risks than estradiol, and Power’s claims of its interest for optimizing the reception of estradiol is still to be proven. Scientifically speaking, Dr Will Power’s method is still considered theory.

2 - SHBG: What is it, and why it can matter

Sex hormones, for the vast majority, don’t run freely in the body. Once they reach the bloodstream, they actually attach to other molecules present in the blood. Most is loosely bound to albumin ( around 54%), another portion is more tightly bound to SHBG (44%). Which leave only 1 to 2% free or “bioavailable” sex hormones. The thing is… only these free estrogens or androgens are active, that is, able to penetrate the cells and produce changes. In other words, albumin, and even more SHBG inhibits the activity of sex hormones.

This can be particularly interesting to know for transfem people using estrogens. Indeed, SHBG levels can vary, and one of the main factors of SHBG increase is…higher levels of estrogens. This mechanism is thought - among others - to be a protection for the pregnant person against the incredibly high levels of estrogens produced during pregnancy, as well the sex hormones produced by the fetus. But in our case it means two things:

• If your levels of estrogens are good, and you testosterone low enough, but you are not experiencing any (or very little) changes after 6 months of HRT, it might be relevant to measure your levels of SHBG, as some people are born with or develop higher than average levels of SHBG. Do not assume, however, that this is the only explanation for your lack of reactivity to HRT; it is one possible reason among others, and the only way to know is to have your SHBG measured.

• Theoretically, significantly increasing the dosage of estrogen can be quite useless, if not lead to counter effects, since it might trigger an increase of SHBG, and hence diminishing the levels of bioavailable estrogens. However, this is only how it would work on paper. In reallity, it seems that it would be quasi-impossible (in the frame of trans HRT) to raise your estrogens levels to the point where SHBG levels gets too high and effectively start blocking the feminizing effects of estrogens. You should not worry too much about this issue when going for high-dose estrogens therapy.

3 - Estrogens

Estradiol is the main active estrogen in our bodies, and has a much higher binding affinity than estrone, so that is the one we will use for feminizing HRT. There are also a number of synthetic estrogens, developed by pharmaceutical laboratories in particular for the use in birth control pills: a common one is Ethinylestradiol (EE). As a synthetic derivative of estradiol, EE also comes with more (and more frequent) side effects. This is why it is not recommended to use birth control pills for feminizing HRT. Actually, research has shown that the common side effects of estrogen therapy that trans women are usually warned about by practitioners - and used as a reason to keep them at low doses of estrogens - such as blood clots, are mostly associated to synthetic estrogens (like EE), and to a much lesser extent to bioidentical estradiol.

Target range

A serum level of 200 to 300 pg/ml is usually enough to activate the negative feedback and efficiently reduce the production of testosterone. If are not on monotherapy, the same range also seems to be a target for most transfem people in order to keep a good mood and energy. However, keep in mind that those values can change between individuals, and the best remains to do blood work, and be attentive to how you feel.

This is especially true for the threshold of “overdosing”, which can vary a lot between individuals. Some trans women need higher doses (between 350 and 600 pg/ml) to feel good, when others will have symptoms of overdose at these levels (headaches, nausea, heavy legs). Find what is good for you, when you feel energized, and don’t hesitate to try to get higher levels if you feel symptoms of underdose (tiredness and fatigue, low morale, hot flushes, complete lack of libido…).

Do not assume this is just your mood and do not normalize it. Adjusting your levels CAN make a difference.

Summary of the different routes

3.1 - Transdermal gel and patches

Estradiol is a good candidate for transdermal administration, meaning that it is rather well absorbed through the skin.

This mode of administration comes in two forms, gel and patches. There is no fundamental difference between the two. The choice is merely a matter of convenience (a daily or twice-daily application of gel, applying the patches once or twice a week). Note, however, that patches are subject to frequent shortages in pharmacies in Europe, and you sometimes need to apply many of them at the same time to reach the levels of estradiol you want, especially if the pharmacy is unable to provide the stronger ones.

In comparison to oral administration, the transdermal way has the advantage of avoiding liver first-pass - that this the quasi-total conversion of estradiol into estrone by the liver after digestion. With transdermal route, estradiol reach the bloodstream directly, without overcharging the liver.

However, there are great inequalities between each individual in terms of skin absorption abilities. Transdermal administration might be very efficient with some, but not with others, who would struggle to reach target levels of estradiol.

Pros:

• Easy and accessible, uninvasive
• Usually gives stable hormone levels if taken with regularity.
• Quite safe in terms of side effects, especially blood-clots (thrombosis)

Cons:

• Doesn’t work great on everybody
• For the gel, you have to let it dry, and be mindful of transfers if you touch people with the skin on which you applied the gel recently
• For the patches: can leave glue marks, irritate the skin, and they tend to fall off in the warm days of summer, with physical activity and warm shower/bath/sauna.

Gel

With the gel “Estrogel”, delivered in a bottle with a measured pump, the dosage is usually given in number of pump pressions.

Each pump pression delivers 0,75mg of estradiol; 4 pressions yelds 3mg…

Patch

Equivalence between doses of patch, gel and pills

Theoretically, of 50µg/day patch is equivalent to a 2mg pill, and to 1.5mg in gel. These values, however, can considerably vary. Once again, the best way to ensure good levels is to do blood work.

How to apply gel/patches

Try as much as you can to apply on clean skin to optimize absorption. Apply on a hairless area (shaved works) Do NOT apply on breast: it does not help with breast development, but might increase the risks of breast cancer. Avoid applying on the inner forearm, as it might interfere with bloodworks results. If you do, start applying somewhere else at least a week before testing blood.

Note that a variant of transdermal route is nasal spray (intranasal). Estrogens are absorbed by the mucous membrane of the nose. This route is found to be more convenient by some people. However, this medication is not available in Sweden; but it can be found in other countries.

What is the scrotal method?

Scrotal method consists in applying the gel on the scrotum (the skin containing the testes). This skin being thinner and heavily vascularized, it leads to better absorption, so higher levels of estradiol for a same dose of gel(up to 6 times higher). Research has been conducted, but we know little on the long term effects of this method.

Some trans women using it report increased fragility of the penile skin, with skin easily breaking at points of frictions. Topical application of the gel on this area might also lead to overly low levels of testosterone, which is not recommended. Testosterone is part of a healthy hormonal balance for all individuals, and participates in maintaining cognitive functions such as memory, among other important functions… If, as a transfeminine person, you will want to stay under 0.5 ng/ml (50 ng/dl), reaching absolute zero (or close to it - under 0,8 ng/ml) is not recommended. Some trans women reported that stopping the scrotal method after using it for more than 6 months both improved the skin fragility, and the overly low testosterone level.

It remains, however, a possible method to use in order to achieve higher levels of estradiol with limited gel supply.

Sources

Testosterone replacement in male hypogonadism

« Due to the superficial vascularity of the scrotal skin, there is a 5-40 fold increase in steroid absorption when compared to other skin sites. »

Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site- -a clinical research center study

« the relative permeability at other application sites was greatest for the scrotum (42.0), increased for the back (1.7), reduced for the lateral ankle (0.42), and lowest for the sole of the foot (0.14). »

Tratamiento del Cáncer de Próstata Avanzado con Estrógenos Transdérmicos Escrotales (ETE). Transdermal Scrotal Estrogen Patches (TSEP) in the Treatment of Advanced Prostate Cancer.

3.2 - Oral

This is a very common administration route, and easy to take.

We should however distinguish two ways to take an estrogen pill: swallowing and letting it melt in the mouth.

Swallowing

This is the easiest way, but also the one associated with the higher risks for your health, as it increases the risks of thromboembolic accidents. These risks, however, remain relative to each individual, and medication has improved greatly since the first versions of estrogen pills that used to be the norm in the transfem community (Premarin, or conjugated equine estrogens).

As stated above, the pills prescribed for HRT (bioidentical estradiol) remain significantly less risky in regards to thromboembolic events than the synthetic estrogens used in birth control medication. (Source)

The higher risks associated with swallowing are to be put on the hepatic first pass - which is the liver dealing with ingested chemicals when they are digested. This stands for any medication taken orally: all of them will mobilize this liver function, and, so to speak, making it a bit more “tired”. As a general rule, it is best to avoid oral medication when possible.

The second reason is another consequence of the liver first pass, but more closely related to estrogen. We talked about it before: the liver converts the vast majority of the swallowed estradiol into estrone. Not only is estrone associated with higher health risks, but it also significantly less potent in terms of feminizing effects.

Pros

• Easy and accessible
• Usually gives quite stable and long-lasting hormone levels

Cons

• Increases risks for health (mainly thromboembolic accidents)
• Usually give low estradiol levels, and higher estrone levels.

Sublingual/buccal method

This is the alternative to keep the pills, but avoid the hepatic first pass and hence the risks associated. It consists in letting the pill completely dissolve under the tongue, or between the inside cheek and gums (a bit like snuss).

This way, estradiol will be directly absorbed by the buccal blood vessels, and reach your bloodstream without passing first by the liver. This usually leads to a much faster absorption , with much higher levels. However, the levels tend to fall down quite fast as well. This “yoyo” effect usually leads people to take a pill every 8 to 12 hours in order to maintain correct levels.

Pros

• Easily gives higher estradiol levels
• Less thromboembolic risks

Cons

• Yoyo effects - having to take a pill every 8/12 hours
• No scientific research on the possible risks of this method (and the consequences of the yoyo effect on feminization/body development)

3.3 - Injections

Injections of estrogens are not very common in Europe. It is, however, a much more common administration route in other countries, namely in the USA, Latin America, and Japan.

Injection - if you don’t have issues with needles - is a very convenient way to reach high levels of estradiol for monotherapy. It allows for longer time between intakes (up to 15 days with estradiol enanthate). It is also relatively cheap as a vial bought on the grey market costs between 55 and 75 $ USD and can usually last for a year (between 4.5 and 6.5 $/month).

Injections are typically performed as Intramuscular or Subcutaneous. It works by leaving a depot (a small reserve) in the muscle or fat tissue. The depot will slowly release the products, which will enter the bloodstream gradually.

We give more detail on the dedicated pages on how to perform those two types of injections.

What is good to know here is this:

• Intramuscular injection means injection inside the muscle tissue. It usually means using a longer needle, which can be a bit more painful and more uncomfortable if you don’t like needles. The muscle tissues being more vascularized, absorption is faster.
• Subcutaneous injections means injecting between the skin and the muscle, in the fat layer. We usually choose a spot with more fat (upper butt…). With less blood vessels, absorption of the depot in fat tissue is slower, which allows for even longer time between injections, and more gradual increase of the levels after injections.

Esters – What are they?

Injections come with slightly different molecules, which will have a consequence on absorption speed and levels of estradiol reached per shot (and hence, the frequency and doses of each injection). What we use for estrogen injections is called an ester.

An ester designates a molecule (here estradiol) that has been esterified; meaning it has been slightly modified by an addition/replacement of a chain of atoms. This technique is used in many medications, in the objective of optimizing the bioavailability of the drug (and how efficient it is in our system). In a way, the idea is to anticipate the fact that after intake, the body will metabolize the molecule into a weaker (or just very different) form. Esterification creates what we call a “prodrug”: an inactive drug taken as such, but that will become active after its metabolization by the body.

Imagine you want to take a molecule we simplify as “AB”. If you take it just like that, the body will metabolize AB into A, and it won’t be exactly what you want. Esterification consists in first turning AB into ABC; then, after ingestion or injection, the body will then metabolize ABC into AB, and you’ll end up with what you want. For this reason (because estradiol esters are metabolized into estradiol), estradiol esters are considered bioidentical estrogens and not synthetic. The active molecule acting on your body remains, at the end, estradiol (E2).

The main esters used for injections are, Estradiol valerate, Estradiol enanthate and Estradiol cypionate.

Estradiol valerate usually leads to a fast and high peak, falling down rather quickly as well. It means more frequent injections, and also a bigger span between high and low (unstable levels)- which can affect your mood. (Note that estradiol valerate is also used for the oral pill Progynon)

Estradiol enanthate gives slightly lower levels (though still high compared to other routes), but lasts longer. This allows for more stable levels, and the possibility to space out injections (once a week for best stability, up to once every two weeks).

Estradiol cypionate behaves similarly with again slightly lower levels.

You can refer to this Injectable Estradiol Simulator, but keep in mind that data is sometimes scarce, and your actual levels can vary greatly. The best remains to check your levels with blood work, and listen to your body and mind.

Pros

• Easily gives high levels of estrogens
• Allows for easy monotherapy and hence avoid androgen blockers
• Lower risks than with oral route
• No difference of absorption between individual (everyone is receptive)

Cons

• Can produce unstable levels (but can be corrected by dose/frequency adjustments)
• Impossible to get through the legal/prescription market.
• It’s an injection (needle fear…)

Please refer to the dedicated page for details about practicing safe injections.

3.4 - Pellets

This is a rare solution, mainly used in Australia. It consists of a pellet implanted under the skin, delivering estrogens steadily and regularly. This route is also used as a contraceptive method, with a different estrogen. The implantation can leave a little scar, and considering the pellet has to be changed after a few months, it is not ideal to have this route as a long term solution - especially if you started HRT early in your life. That is why it is mostly proposed to post-menopausal women.

Pros

• Delivers steady levels of estrogens, and once in place, you’re good to go for a few months, without having to remember to take your medication

Cons

• Can leave scars, accumulating with years
• You need to see a doctor everytime you change it
• Can sometimes (though rarely) “detach” and circulate in the body (and is sometimes lost)
• You can’t be sure the dosage will be optimal before you put it, and then have to wait a while before correcting it if it is not.

3.5 - Sources on the risks of thrombosis

Transdermal delivery of bioidentical estrogen in menopausal hormone therapy: a clinical review

Pharmacology of estrogens and progestogens: influence of different routes of administration

Menopausal hormone therapy and venous thromboembolism

Oral Contraceptives and HRT Risk of Thrombosis

Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects.

Therapy Insight: parenteral estrogen treatment for prostate cancer—a new dawn for an old therapy

4 - Androgen blockers and progestogens

In order for estrogens to be efficient, the action of testosterone MUST be blocked, one way or the other.

If monotherapy does not work for you, the solution can lie in anti-androgens, or androgen blockers - sometimes only refered to as blockers. Blockers actually encompass a great variety of medications, working in differents ways.

It is usually considered that orchiectomy or vaginoplasty allows for stopping anti-androgens, but not estrogens. It is in reallity a bit more complicated, and you can refer to the page on DHEA and intracrinology to know more about this issue.

Summary table of androgen blocking alternatives

We can sort androgens blockers in 4 groups, according to their mode of actions:

• Androgen receptor blockers (Bicalutamide, Spironolactone)
• GnRH agonists and antagonists (also called Puberty blockers)
• Inhibitors of 5a-reductase (Finesteride, Dutasteride)
• Progestogens (among which Cyproterone Acetate or Androcur) We will now go through all of them, group by group.

4.1 - 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.

4.2 - 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.

4.3 - 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.

4.4 - 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…

5 - Progesterone

Progesterone has relatively few and minor effects on the body, compared to estrogens. Its effects and secondary effects are, besides, still debated among the trans community and medical practitioners and researchers; and the observed effects are sometimes contradictory. If you decide to start taking progesterone, try to be attentive to how it makes you feel, and stop if you feel negative effects as it will most likely affect you more negatively than positively.

Considering that the scientific community seems undecided on the fact that it helps with breast growth (and shaping), and that it could also hinders breast developpement if taken too soon, our recommendation remains to avoid this risk by waiting to reach stage 3 of Tanner scale before taking progesterone.

Start gradually with 100 mg, and consider increasing to 200 mg if you notice positive changes, and/or it helps with your mood.

As opposed to synthetic progestogens, bioidentical progesterone has a very short half-life (the measure to count how long the molecule is active in the body before metabolization/evacuation). In barely a few hours, swallowed progesterone is entirely eliminated by the body.

Besides, when taken orally, progesterone is nearly completely metabolized into allopregnanolone (and to a lesser extent other molecules). This can be responsible for psychoactive effects, similar to low doses of alcohol: somnolence and drowsiness, slight euphoria and relaxation, vague sensation of “being high”. If this can be a disturbance by some, others actually enjoy those effects, especially in cases of insomnia, as taking the progesterone capsule orally right before going to bed might help.

If you seek the actual (possible) effects of progesterone (possible help with breast development and shaping…), the rectal way is the best. Several progesterone medications (Utrogestan, Luteus) presents themselves as a soft capsule or pill that can be inserted in the vagina. In a lack of vagina, the rectal tissue will work similarly. If you got a vaginoplasty, keep using the rectal way as the neovaginal tissue (penile skin in most cases) won’t be as absorbent as the rectal mucous tissues. In practice, simply insert the capsule in the rectum before going to bed. Diffusion will last longer, and the progesterone won’t be eliminated as quickly and metabolized into allopregnanolone.

Some practitioners prescribe topical progesterone as a gel, to apply directly on the breast. If topical application of estrogens on this area is very unadvised (it might only increase the risks of breast cancer), the same technique with progesterone does not seem to cause this problem, and instead enhances breast development. Keep in mind that the technique remains experimental, and mostly practiced in the US by Dr Will Powers, whose method (with its limits) are described here. Besides, topical progesterone gel is not directly available in Sweden, and access to it is conditioned by a practitioner and a pharmacy willing to prescribe and produce a compounded drug for you. However, some DIY suppliers propose progesterone gel.

These are the main possible effects of progestogens:

• 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).

6 - Maintaining erections and healthy penile tissue: topical testosterone

Feminizing HRT will most likely cause a decrease - if not loss - of erections, and primarily spontaneous erections. If this comes with joy and helps with genetital dysphoria for many, some might want to prevent this phenomenon, for different results: desire to maintain sexual practices that requests erections, or avoiding as much as possible penile tissue atrophy.

Indeed, spontaneous erections are a way for the body to keep the penile skin and inner tissue elastic and resilient to friction and minor wounds. With the disappearance of androgen impregnation in these tissues, you might experience pain during erections, and more fragile skin. As described here, the scrotal method of applying gel seems to increase this phenomenon.

“This cream is applied topically to the penis/scrotum once a week at bedtime in AMAB people experiencing erectile dysfunction, painful erections, tissue atrophy (shrinkage and thinning of the skin). It is used with an escalating frequency approaching SRS for optimal tissue health. Post SRS it can be used weekly during a dilation session (by coating the dilator) and sometimes can help achieve additional depth due to increasing tissue elasticity.” “This can be done without increasing systemic levels or causing re-masculinization if you use my compounded formulation, which is 1 gram of compounded 0.5% topical testosterone topically to the penis and scrotum once weekly. It tends to raise T levels about 10-20ng/dl with weekly administration.”

If you manage to have it prescribed, you will most likely need to get the medication compounded for you, as the weakest gel available in Sweden has a 1.62% concentration, when what Dr Powers suggests is a 0.25% to 0.5 % concentration (2.5 mg to 5mg/g).

7 - That was a lot... So, what should I take?

However, if we were asked to propose an ideal treatment, this is our suggestion:

• Always consider starting with monotherapy, and see if you manage to sufficiently bring down your testosterone levels to 0.5 ng/ml (50 ng/dl). For routes of administration, we recommend transdermal gel or injections. With the gel, consider using the scrotal method to efficiently bring down your T - it can otherwise be difficult to have an efficient monotherapy. First, avoid it, and see with blood works if this works. The negative feedback (the mechanism of blocking T with E) starts at around 200 pg/ml. Consider staying between 200 and 600pg/ml of estradiol. If using injections, refer to the Injectable Estradiol Simulator as the dosage will differ depending on which ester you are using. Note however that this simulator is based on avarages, and your levels can greatly vary from the estimation. A blood test is always necessary to monitor your levels.

• If your testosterone is not sufficiently brought down by E2 (i.e. it remains over 0.5ng/ml), consider using a blocker. We recommend bicalutamide or GnRHa (leuprorelin/triptorelin). Keep in mind that it is not necessary and not recommended to bring down your T to absolute 0. Cis-women with typical hormonal balance have T (between 0,08 and 0,50 ng/ml), and it is necessary to maintain cognitive functions (memory…), among other functions. Staying anywhere under 0.5 ng/ml will not bring any masculinizing effects. Also keep in mind that bicalutamide will not lower your levels of T, only its effects. Your blood values will be the same.

• If you still notice masculinzing features - especially on the skin - Bicalutamide can make a difference by preventing the androgenic effects the adrenal activity (conversion of DHEA into androgens in the target cells of the skin - see the page on “Intracrinology”)

• Add 100mg to 200mg progesterone after around 2 years of HRT (or reaching Tanner 3 in breast development), ideally taken in the rectum.

• Use topical weak testosterone gel/cream if you want to maintain erectile function, or prevent penile pain and atrophy, and 6 months before SRS.