Transfem HRT Guide

Introduction

What is Hormone Replacement Therapy (HRT)?

Hormone Replacement Therapy is a broad range of treatments using a variety of drugs that all have one simple goal: to reduce Androgens (such as Testosterone) and increase Estrogen to standard female levels. Originally pioneered in the early 1940s to counteract the effects of menopause in older women, significant research didn’t begin until the early 1970s when it was found that existing options came with significant cancer and clotting risks. It was around this time doctors started to realise the process could be used in AMAB Transgender people for its feminising effects.

Is HRT dangerous?

No drug or medical procedure comes without risks, however, using modern best practices the chance of side effects and rate of adverse events is extremely low. Weighed in a cost/benefit analysis against the high transgender suicide rate, incidence of depression and other mental health issues common in transgender individuals, and the extremely low rates of regret it is - to put it mildly - unquestionably beneficial.

The risks that have been found to occur at statistically observable rates in studies fall broadly into 3 categories:

1. VTE/Clotting (e.g. DVT, Stroke, Pulmonary Embolism, etc)

2. Cancer (particularly Breast Cancer)

3. Thyroid, Kidney and Liver function

These are not general risks of the process, but instead of individual drugs used. Older drugs used in the 70’s and 80’s no longer prescribed today are mostly responsible for the negative reputation. All of these risks have been largely eliminated through the use of bioidentical hormones, non-oral administration and screening via blood tests.

A wealth of studies over the last few decades have concluded that the clotting risks are almost entirely associated with the use of Conjugated Estrogens originally introduced in the 1940s, to a lesser degree with Synthetic Estrogens such as Ethinylestradiol, and are almost (though not entirely) eliminated by using Bioidentical Estrogens and further reduced through non-oral (particularly transdermal) administration.

Cancer risks largely follow the same theme, meanwhile the Thyroid, Kidney and Liver risks are mostly associated with high doses of particular antiandrogens such as Cyproterone Acetate and Spironolactone.

What does HRT do?

Achieving female hormone levels will have an overall feminising effect on the body. This includes changes to skin, hair, nails, sweat, facial features, fat distribution and breast growth.

Often understated however are the mental effects. Though not well studied in the micro there is a wealth of anecdotes within the transgender community describing positive changes to aggression, emotions, thinking patterns, sexuality, and even sexual orientation. In the macro there is clear statistical evidence that there are overwhelmingly positive outcomes on mental health and an overall improvement in quality of life.

How long does it take?

Due to a lack of consistency in regimens, targets and recording by medical professionals, it is almost impossible to judge this objectively. Based on experiences shared within transgender internet communities a good rule of thumb is that many of the visceral mental effects such as reduced aggression and libido occur within the first couple of weeks and other mental changes follow over the next few months, while the physical effects develop gradually over 2-3 years, finalising around the 5-year mark.

Sex Hormones

Since HRT involves manipulating sex hormone levels it’s good to have a brief high-level understanding of them.

At a basic level, there are three primary groups we are interested in: Progestogens, Androgens and Estrogens. Estrogens are female hormones, Androgens are male hormones, while Progestogens are a more complicated family that play an important role in - among other things - reproductive function in AFAB individuals. We generally discuss Estradiol and Testosterone levels specifically when talking about HRT, but it should be understood that we are suppressing the group as a whole. This is particularly important when discussing 5-alpha reductase inhibitors and DHT, the main exception to this rule.

Estrogens

Estradiol

The primary Estrogen. Bioidentical Estrogen is always taken in the form of Estradiol.

Standard Adult Male Range: 50-200 pmol/L
Standard Adult Female Range: 70-510 pmol/L (range varies widely over ovulation cycle)
Source

Estrone

Estrone has 4-8% of the Estrogenic activity of Estradiol. Estrone levels are regularly increased by using oral administration and there is some limited evidence linking increased amounts of it with VTE and Cancer risks.

Androgens

Testosterone

Testosterone is the primary male hormone and the primary source of androgenic activity.

Standard Adult Male Range: 11-36 nmol/L
Standard Adult Female Range: 0.8-3.1 nmol/L
Source

Dihydrotestosterone (DHT)

DHT has 200-300% of the androgenic activity of Testosterone. Its primary role in the human body is in sperm production within the Testes, however, it is also strongly associated with male hair patterns including both the development of facial/pubic/body hair and male pattern baldness. DHT represents a small and generally quite localised portion of the overall androgenic activity within the body and in the context of HRT, its reduction should not be seen as a goal in and of itself beyond attempting to reverse male pattern baldness.

Progestogens

Progesterone

Progesterone is a key signalling agent in AFAB reproductive function. Most female birth control takes the form of high-dose Progesterone. It has anecdotally been observed to have some positive effects on breast development in HRT, though hard evidence for this is lacking.

Hypothalamic Pituitary Gonadal (HPG) Axis

The HPG axis is the primary regulation mechanism for Sex Hormone production. At a basic level it works like this:

1. The Hypothalamus monitors sex hormone levels and produces GnRH when they drop too low.

2. The anterior pituitary gland is stimulated by GnRH to produce Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH).

3. The gonads are stimulated by LH and FSH intro producing Testosterone in AMAB individuals or Estradiol and Progesterone in AFAB individuals.

Recommended Regimens

Based on level stability, safety, compliance and cost there’s a fairly clear hierarchy of optimal regimens. You can choose any of these regimens and be happy with them, but if you plan to use one further down the list it should only be done after carefully considering the downsides in regards to your personal circumstances.

Estradiol Injection Monotherapy

A subcutaneous injection of estered Estradiol approx weekly. Estradiol has a biological half-life of ~4 hours and will be entirely out of your system within 24-36 hours however esterification extends this making it a slow-release dose, Estradiol Enanthate (EEn) for example has a biological half-life of ~6.5 days and takes 4-5 weeks to be entirely flushed out of your system. A weekly injection of 4mg EEn will bring almost anyone to Estradiol levels high enough to shut down Testosterone production without the use of a blocker by taking advantage of the HPG axis we discussed above, acting on the Hypothalamus and satisfying its target for sex hormone levels.

This regimen ticks a lot of boxes. First, the injection is done with a tiny needle not into a vein but into the fat layer right underneath the skin, typically in the buttocks or abdomen just like the insulin injections that many diabetics perform as a normal part of their daily routine. While self-injecting can seem scary at first it’s just a simple 5-minute routine once per week, easily maintained and not a big deal if it’s missed by a few hours or even a day or two.

While other administration methods will see large variations throughout the day and a huge spread from person to person in what dose is required to reach certain levels, injections provide highly stable and predictable results. This makes recommended starting doses and judging blood tests very simple, perfect for DIY where many are paying out-of-pocket for every test and trying to minimise how many are needed.

Lastly, it’s cheap. DIY injectables are almost always homebrew and 2 years of supplies can easily be bought for around $150. Many in our community struggle financially, given the importance of HRT this cheapness is life and death for many.

Transdermal Gel + Blockers

Transdermal gels are rubbed on the skin and absorbed within a few minutes, done daily. This is combined with an oral blocker also taken daily, usually Cyproterone Acetate though Bicalutamide or Spironolactone work well too.

While it lacks the stability and predictable dosages of injections it has no problem achieving good enough levels and avoids the liver conversion issues of pills. Theoretically, monotherapy is practical with gel but in practice the margin of error for letting them get too low is so thin that it’s not taking the chance. Miss your dose by half a day or get into a habit of spreading it too thin and you can find your Testosterone levels starting to rise again.

It’s also physically safer since no needles are involved and similarly cheap since Gels are increasingly sold by the same homebrew providers that make the injectables.

A starting Estradiol dose of 3-4mg/day will work for most though this should be tweaked in response to blood tests. For blockers 12.5mg/day Cyproterone, 50mg/day Bicalutamide or 200mg Spironolactone will do the job, no testing necessary.

As a final note there’s a common suggestion floating around the community that gels can be applied to the scrotum for optimal absorption. This isn’t an old wive’s tail, there is a study showing higher absorption and it’s well studied with Testosterone however it also results in a much greater spike. It’s a higher level shortly after, but it also falls off a lot faster which works against our goal of stable levels. If you want higher levels then just take a higher dose, it’s that simple, there’s no need to cheat.

Estradiol Pills + Blockers

The main downsides of Estradiol pills compared to other administration methods are extremely poor absorption and rapid elimination from your system, most of it is destroyed in the liver and it’s entirely out of your system within 24-36 hours. This results in needing to take relatively large doses multiple times per day to maintain target levels.

Pills should be taken at least twice per day, ideally thrice. If taken once per day in the morning you’ll find yourself towards the end of the day feeling quite lethargic and though it’s not been studied or quantified this almost certainly negatively impacts feminisation since you’re below target levels for most of the day.

Sublingual pills (allowing them to dissolve under the tongue and be absorbed) aren’t recommended for essentially the same reason as explained above with scrotal gel application. It does circumvent much of the destruction in the liver but it also flushes through the system even faster which is already a problem with pills. Again if you want higher levels it’s better to just take a higher oral dose.

An Estradiol dose of 4-6mg/day is a good starting point. The pills are almost universally 2mg, so one pill every 12 hours or every 8 hours is the way to go. When getting blood tests try to get it taken as close to the trough as possible, right before your next pill.

Blockers are the same as recommended for gels. 12.5mg/day Cyproterone Acetate, 50mg/day Bicalutamide or 200mg/day Spironolactone.

Honorable Mentions

• Transdermal Patches + Blocker: This regimen is in many ways superior to gel as patches release Estradiol at a stable rate and are more easily complied with assuming no sensory issues. However, as of late 2023, patches have been almost entirely out of stock through most grey market sellers for over a year and even regular pharmacies are having massive supply issues. It’s a result of a manufacturing shortage that isn’t likely to be fixed any time soon so the reliable access simply isn’t there.

• Any Method + GnRH agonist: GnRH agonists are the ideal blockers, however they are extremely expensive and difficult to source from grey market sources. Their upsides simply don’t merit the cost when your wallet is footing the bill.

• Any Method + Finasteride/Dutasteride: As explained further down these 5-Alpha Reductase Inhibitors are not proper blockers. You can take them if you have reason to do so, but it should be in addition to a real blocker or a monotherapy regimen.

• Progesterone + Anything: Likewise Progesterone is not a substitute for Estradiol or a blocker, it should be taken in addition to these things, not as a substitute.

• Ethinylestradiol: This is a synthetic Estrogen that comes with statistically significant health risks and based on the well-studied fact that it has different potencies in different areas of the body it’s likely not even as effective for feminisation as bioidentical Estradiol. There’s no reason to take this.

• Premarin: Similar to Ethinylestradiol, higher risks for no upside. Do not take this.

• Blocker-only: While this is the common approach for puberty blockers it has both long and short-term health effects. The goal with these regimens is usually some form of non-binary HRT but the endocrine system just doesn’t work that way. Your body needs one dominant sex hormone to function properly.

• Tamoxifen/Clomifene/Raloxifene (SERMs): There are stories within the community of using these drugs as part of a non-binary or femboy regimen to prevent breast growth. While in theory this should work these drugs are too toxic to the liver to take long term. Transition is different for everyone but starting HRT is ostensibly a commitment for the rest of your life and on that timescale they will almost certainly cause some level of permanent liver damage. Again while gender isn’t binary the endocrine system by our current understanding is, and if you’re uncomfortable with certain aspects of HRT it’s better to work through that with a therapist or close friends.

Blood Tests

Baseline

There’s often an undue level of importance placed on baseline blood tests. If you have or suspect you may have any conditions that have contraindications with the HRT medications you plan to take then it’s worth getting tests for those conditions so they can be monitored, but there’s almost nothing actionable to derive from baseline sex hormone levels. Suppose your test shows you have unusually low Testosterone or higher than expected Estradiol levels for an AMAB person, what do you do with this information other than go “Huh, interesting”? It could indicate some sort of intersex condition or hypogonadism but it doesn’t imply any danger nor will it affect your starting dose, you’ll just keep an eye on it in later blood tests which you would have done anyway.

If you have cheap and easy access to blood tests through a supportive doctor or a harm reduction organisation and it’s not going to significantly delay your start date then go for it, but if you’re going to be waiting months or it’s stressing an already tight financial situation then don’t worry about it.

Units

Several different units of measurement are used for different hormones and in different countries.

Estradiol in North America is typically measured in picograms-per-milliliter (pg/mL) while internationally it’s measured in picomoles-per-liter (pmol/L). 100 pg/mL = 367 pmol/L or as a quick mental shortcut, “pmol/L is 3.5x pg/ml”.

Testosterone in North America is typically measured in nanograms-per-decliliter (ng/dL) while internationally it’s measured in nanomoles-per-liter (nmol/L). 50 ng/dL = 1.73 nmol/L, no easy mental shortcut here.

To further complicate this the molar concentrations (nmol and pmol) are dependent on the molecule being measured, so 2 nmol/L of Testosterone and 2 nmol/L of Estradiol refer to different amounts of the chemical.

Transfemscience has a handy calculator here to convert between all of these units but our suggestion would simply be to memorise target levels in the unit used where you live and not worry about it unless advising someone else, in which case pull out the calculator and double check.

Target Levels

Optimal target levels are a subject of vigorous debate both online within the trans community and offline within the medical establishment however it’s almost entirely conjecture, there isn’t a single study that objectively measures physical changes against hormone levels. All we have to go off are normal levels in AFAB people and anecdotes from within the community about what different levels have achieved for them. This isn’t to express doubt on the following recommendations nor cast aspersions on other recommendations, but simply to point out that all anyone has until those studies are performed are working theories, as evidenced by everyone recommending nice clean rounded numbers in their local unit of measurement. Any claim to authority on this subject should be treated with intense scepticism.

WPATH SoC v8

The WPATH Standards of Care Version 8 recommend a Serum Estradiol of 100-200 pg/mL (367-734 pmol/L) and Serum Testosterone of less than 50 ng/dL (1.73 nmol/L). Tests should be taken every 3 months for the first year, then 1-2 times per year thereafter. They also recommend monitoring potassium and kidney function depending on the blockers used and the method of administration.

UCSF

The UCSF Transgender and non-binary care guidelines defer to guidance from the Endocrine Society which simply says to match mid-cycle levels in cis women. Depending on the reference ranges we look at this gives us a similar ~150 pg/mL (551 pmol/L) Estradiol target to the WPATH guidelines, but a lower ~40 ng/dL (1.39 nmol/L) target for Testosterone.

Additional UCSF recommends a trough of 50 pg/mL (183 pmol/L) and a peak of 250 pg/mL (918 pmol/L) when using injections. This guidance is in light of the fact that many patients in North America use Estradiol Valerate injections on 2 weeks cycles, resulting in a large variance in levels across that time.

NHS

In the UK the NHS Gender Identity Clinics use a variety of target numbers in different geographical locations, but they are all downstream of guidance from the Consultant Endocrinologist Dr Leighton Seal at Tavistock. These guidelines have at times included multiple false assertions such as reverse aromatase (the conversion of Estradiol back into Testosterone) which are easily refuted by any endocrinology textbook. They also make wildly unrealistic recommendations on starting dosages and suggest rates of titration that would result in most patients taking years to reach the 400-600 pmol/L (109-163 pg/mL) target guidelines.

There are a wealth of credible accusations within the UK trans community that Seal, when challenged on this in private, believes that these long titration periods and lower levels result in better outcomes without any evidence and give a patient who shouldn’t be transitioning a chance to “prove” that it’s really right for them. These accusations are supported by it being almost standard practice in British private trans healthcare organisations for psychologists to order the patient’s dosage be limited to an almost placebo level until they’re satisfied with the progress of the patient’s social transition. This practice is completely unprecedented internationally, completely unfounded in evidence, rejected by WPATH internally and largely regarded as an attempt to appease transphobes espousing the Rapid Onset Gender Dysphoria conspiracy theory.

As they are so far out of line with more rigorously achieved international guidance and a source of complaint for so many patients, the NHS guidelines can be entirely disregarded.

Dr Will Powers

Powers is a family doctor in Michigan who has produced many theories on trans medicine with varying degrees of credibility. His most popular guidance includes a target Estradiol range of 100-300 pg/mL (367-1101 pmol/L) and Testosterone of less than 50 ng/dL (1.73 nmol/L). While Powers has some more bombastic claims regarding Estrone and SHBG these suggestions are largely in line with more reputable guidance and there are plenty anecdotes online of patients benefiting at least psychologically from these higher levels.

Female Reference Ranges

As a final consideration, it’s worth looking at female reference ranges. A Google search will turn up many slightly varying results, but we’d recommend these values from the Irish Health Service Executive as representative and reputable.

Our Recommendation

Coming full circle we’re happy to endorse the WPATH guidelines of 100-200 pg/mL (367-734 pmol/L) for Estradiol and <50 ng/dL (1.73 nmol/L) for Testosterone. They’re known safe values in regards to broader health concerns, they clearly work given they’re what we see in cis women, and after seeing hundreds of blood tests and helping many trans people over the years, it’s clear to us that the overwhelming majority are happy with what they get from these levels in the long run. We would however add one caveat:

You should aim for the upper end of this range and not be scared to exceed it at peak. In patients using transdermal patches where the level is essentially a flat line, it’s common to observe complaints of lethargy and low libido if the patient is sitting at the lower end of this spectrum, and then find those complaints are resolved when they titrate up to a higher dose. Rather than considering anywhere in that window the goal, treat it like an archery target where 200 pg/mL is the yellow center and 100 pg/mL is the edge of the target. If you hit the target it’s a good enough shot, but you’re always aiming for the center.

Anti-androgens (AAs)

Most HRT regimens begin with the use of an antiandrogen (often known as a “blocker”) to suppress Androgens directly. It should be noted Estradiol alone functions as an AA by stimulating the Hypothalamus and slowing down the HPG axis. The amount required to achieve this varies wildly from person to person but it’s important to note that if Estradiol alone achieves this, an AA is usually unnecessary.

Spironolactone

Spiro is a widely used and extremely cheap drug first introduced in 1959, it is a potent anti-mineralocorticoid, a mild AA and a weak steroidogenesis inhibitor along with a few other minor interactions. It has been used successfully in the treatment of heart failure, high blood pressure and prostate cancer.

Since its AA effects are quite weak compared to many alternatives it is typically taken at much higher doses. It functions primarily by blocking Androgen Receptors throughout the body, inhibiting Testosterone and other Androgens from successfully binding to and activating the receptors. Its function as a weak steroidogenesis inhibitor can also cause a reduction in overall sex hormone production, though the doses required to achieve this have only been tested in animals and results in human trials have been rather inconsistent. It has also been observed to slightly increase Estradiol levels through mechanisms that aren’t entirely clear.

In feminising HRT Spironolactone is widely used for its AA properties, particularly in the United States where CPA isn’t FDA approved, and typically prescribed at dosages of 100-200mg/day.

The primary side effects of Spiro are raised potassium levels in 10-15% of patients, weight gain and diuresis (increased urination).

There is a growing consensus in transgender healthcare that Spiro - while being a generally safe drug - comes with greater associated risks and a wider range of side effects than other options while being no more effective. It has also been statistically linked with reduced breast growth in transgender women.

Cyproterone Acetate (CPA)

CPA is a widely used and extremely cheap synthetic progestin used exclusively for its potent effects as an AA, first introduced in 1973. It has been widely used in AFAB birth control pills, used successfully to treat a variety of conditions relating to excessive androgen levels in both AMAB and AFAB individuals, and in Androgen Deprivation Therapy (ADT) to treat Prostate Cancer.

As an AA, CPA functions by having a strong effect on the Hypothalamus, significantly reducing GnRH production and effectively shutting down the HPG axis.

In Feminising HRT CPA is widely used in Europe, Australia and Latin America, typically at doses of 12.5-25mg/day.

Though well tolerated, the primary side effects of CPA are mild depression, vitamin B12 deficiency, hepatotoxicity, increased prolactin levels and on rare occasions benign brain tumours. It is also worth noting that these side effects are mostly commonly found when used in ADT at significantly higher doses than the 12.5-25mg/day most commonly used in HRT.

CPA is generally considered to be a safe and effective AA as part of an HRT regimen. When available it is generally considered a preferable alternative to Spironolactone due to its milder side effect profile.

Bicalutamide

Bicalutamide is a Nonsteroidal antiandrogen (NSAA) first introduced in 1995. It is a derivative of Flutamide and appears on the World Health Organisation’s list of Essential Medicines, the safest and most effective medicines needed in a health system. It is most widely used as monotherapy ADT to treat Prostate Cancer.

As an AA, Bicalutamide functions by indiscriminately blocking Androgen Receptors throughout the body. While this does not reduce Androgen levels in the blood, it almost entirely inhibits their ability to affect the body’s biological functions.

Bicalutamide is remarkably well tolerated and except for Liver toxicity in less than 0.1% of patients, it comes with almost no significant risk of side effects. The side effects noted when used at higher doses of typically 150mg/day in ADT include Gynecomastia, reduced libido, and loss of erectile function, all directly attributed to lower Androgen levels and desired outcomes for our purposes in feminising HRT.

There is a working theory that Bicalutamide’s AR blocking mechanism increases the sensitivity of Estrogen receptors due to its use at high doses as a monotherapy having Estrogen-like effects on the body, however there are currently no studies to support this.

GnRH Agonists

Triptorelin, Goserelin and Leuprolide are all widely used GnRH agonists introduced in the mid-1980s that achieve a complete shutdown of the HPG axis by overstimulation of the Pituitary Gland, rendering it insensitive to the body’s naturally produced GnRH. They are used for a variety of conditions, most commonly androgen-sensitive cancers. They have also been used to chemically castrate sex offenders. The mechanism by which they work makes them equally effective in hormone shutdown for both AMAB and AFAB individuals.

Triptorelin under the brand name Decapeptyl is the preferred Antiandrogen of the NHS’s network of Gender Identity Clinics. Leuprolide under the brand name Lupron is commonly used in the US as a “puberty blocker” for gender questioning children and teenagers.

GnRH agonists are generally considered the most effective method of Androgen suppression, allowing for a complete shutdown of the HPG axis at safe and widely studied dosages. Unlike other Anti-Androgens discussed in this guide which are administered in the form of (usually daily) oral pills, GnRH agonists are delivered as monthly or quarterly Intramuscular injections. While largely interchangeable in safety and effectiveness, Triptorelin has shown to be slightly more effective in studies.

If available, a GnRH agonist is the preferred method of androgen suppression.

Finasteride

Finasteride is a 5-alpha reductase inhibitor introduced in 1992 widely used against Prostate overgrowth and Androgen-sensitive cancers, but mostly commonly used as a palliative treatment to slow or stop male pattern baldness.

As an AA, Finasteride functions in a limited capacity as a 5-alpha reductase inhibitor. As can be seen here 5-alpha reductase is the process by which Testosterone is converted into Dihydrotestosterone (DHT).

Finasteride is widely prescribed by several private Transgender healthcare providers in the UK (notably GenderGP) as a general Antiandrogen under the pretence that it will reduce Testosterone and all Androgens equally, this is entirely untrue. It actually causes a minor increase in serum Testosterone levels, a finding replicated across a wide number of studies.

While generally safe and well tolerated, Finasteride is widely associated with a high incidence of depression. Given the already high levels of depression and suicidality in the transgender population this should give serious food for thought when considering the use of this drug.

Finasteride is an effective method of treating male pattern baldness, a concern naturally important to transgender individuals interested in feminising HRT, however it should be understood that given the suppression of Testosterone and overall Androgen levels by Estrogens and/or other Antiandrogens, it is largely unnecessary as a component of feminising HRT regimen.

“Homebrew” vs Pharmaceuticals

Homebrew drugs are manufactured by individuals or small groups of trans people looking to do their part to help the community. These groups will purchase Estradiol or another active ingredient from a wholesale supplier in its raw powder form and manufacture it into whatever form is ultimately taken by a person such as an injectable oil, a swallowable pill, etc. It’s important to understand the risks, there is a non-zero possibility of contamination or problems with the manufacturing process because these folks simply do not have the same resources that a multi-million dollar pharmaceutical company has.

On the other hand, the most trusted suppliers are eminently educated on these subjects often working in or adjacent to the pharmaceutical industry, or at the very least operating on guidance from others who are. If you’re interested in reading more about this the guidance at hrtcafe.net explains in intricate detail every single aspect of the process and most suppliers have a process largely comparable to that. At diyhrt.market we can vouch for having had this reviewed by a professional in the biomedical industry. Sites like this one and diyhrt.cafe vet suppliers, making sure there are months worth of satisfactory feedback from customers before listing anything from them. There have in the past been a very small handful of suppliers who have not reached that quality bar and been rejected by the community, so we know this community consensus approach works.

Put simply, homebrew drugs from suppliers listed here are safe and effective within the constraints of reasonable concerns, but we do believe it’s important that you know what you’re getting.