Estradiol Monotherapy FAQ

WARNING: I AM NOT A DOCTOR

I will be providing sources from actual medical studies and doctors, however.

1.1 How does injected Estradiol Monotherapy work without an anti-androgen?

Estradiol in high enough doses suppresses testosterone ¹.

1.2 What are the advantages of injected Estradiol Monotherapy?

• The number one advantage over other forms of DIY HRT is the cheapness. In UK currency as of 25th August 2022 over a year and a half's supply of injectable estradiol, syringes and (optional) alcohol wipes is ~£90 (~US$107). Some additional fees may be incurred due to the costs of cryptocurrency required to pay for this but if paid in bitcoin these should not be too hefty.
• If endocrinologists are not adequately suppressing your testosterone (e.g. with a weak anti-androgen like spironolactone) then studies show that injected monotherapy definitely achieves this ¹. This being said however, both cyproterone acetate and bicalutamide with sublingual estradiol can similarly achieve this without the speculative problems seen in Section 2.
• Estradiol monotherapy is safer than anti-androgens for long term DIY HRT (the obvious reason being: one will always be on a source of estradiol, but adding an anti-androgen naturally introduces more risk factors) and transfeminine people can stay on it indefinitely. Anti-androgens aside from perhaps spironolactone are not to be used long term without a doctor due to potentially adverse side effects e.g. cyproterone acetate and benign brain tumours ², bicalutamide and rare fatal liver failure or lung damage ³ . Spironolactone is safe long term, but as mentioned in Question 2, spiro is such a weak anti-androgen that it will likely not suppress testosterone well enough for much feminisation to occur. Do note that cypro and bica may be fine if one has an endocrinologist to monitor for potentially dangerous side effects, but otherwise the general advice I have heard is not to stay on these for more than a year.
• In fact, estradiol monotherapy (whether injected or sublingual) is safer than oral estradiol in terms of liver issues. This being said, however, this is actually true of most routes of estradiol intake which are NOT oral ⁴ .

2. Will this stunt my breast growth?

Note that in general transfeminine people who desire breast growth will usually eventually switch to injections (for the ease of scheduling doses at least), from my general knowledge, after 6 months to 2 years or so oral or sublingual estradiol and an anti-androgen. This is because certain studies have witnessed most breast growth occurring in the first 6 month period (e.g. here ), although we caution that such studies often do not last longer than 3 years. If there is a stunting risk from injected monotherapy, then this stunting risk is thought to only be applicable early on in transition. However, this risk is itself controversial due to the lack of human in vivo evidence. There are two contrary points to keep in mind:

1. Injected Estradiol monotherapy is likely far better at suppressing androgens than spironolactone. Spironolactone is a poor anti-androgen and yet widely prescribed as opposed to cyproterone acetate or bicalutamide in some countries. Studies have shown that many trans women on spironolactone (up to 75%) ⁵ do not have adequate testosterone suppression, and in fact to some extent what little is suppressed appears to be due to the oral estradiol instead. Meanwhile, injected estradiol monotherapy doses achieving blood levels of >200-300pg/mL) definitely suppresses testosterone well ¹ . Suppressing androgens in general appears to be the most important part of achieving a desirable hormonal transition.
2. There are multiple studies linking overly high doses of estradiol to reduced mammary gland ductile growth in animals such as rodents, rabbits and monkeys, and in vitro human breast cells. ⁶ . Not only are rodents useful models for human endocrinology ⁷ , but the in vitro studies draw support for the possibility that overly high doses of estradiol inhibit breast growth; in particular the study in question claims that too much beyond a 'sweet spot' dosage will have less of an effect. There is an obvious problem however with extrapolating exactly how high a dose of estradiol is needed to inhibit breast growth in transfeminine individuals however.

Anecdotal data and guidance in DIY communities tends to focus more on the latter viewpoint, but all the data are skewed in general by the lack of individuals who start on injected monotherapy. The general wisdom is that, in mimicking estrogen levels during puberty, one should start out with low "area under the curve" routes of administration of estradiol such as oral or sublingual. This necessitates an anti-androgen, as oral estradiol will not suppress testosterone alone and sublingual estradiol's short half-life means androgens will not be suppressed at night when one is sleeping.

A huge confounding factor here also is that most transfeminine individuals who desire breast growth are injecting far too much estradiol. Transfemscience points out that blood levels of 200-300pg/mL estradiol is all that is required to adequately suppress testosterone ⁸ , and certain discords have even stated that 100-200pg/mL may be sufficient for some. We do not know the actual values of estradiol required to suppress breast growth in vivo in humans, nor do we even have studies showing that this definitely occurs, but given above 400pg/mL is already hitting supraphysiological levels, that is to say, levels cis women do not regularly attain, then any breast suppression effects anecdotally noted may be due to the very high doses often recommended by manufacturers.

Extrapolating much from anecdotes obviously must be cautioned against, because weighing contradictory anecdotes appropriately becomes difficult. There are examples of great breast growth from injected monotherapy in reddit timelines, and many nonbinary transfeminine people using high dose injected estradiol monotherapy specifically with the goal of suppressing breast growth may fail to achieve this goal.

3. Should I inject into muscle or into fat (subcutaneous)?

4. Where do I inject?

I believe you should inject subcutaneous into the abdomen or the thigh.

There are two schools of thought on this. One is that with the small needles (insulin needles essentialy) used for estradiol monotherapy one is not at risk of hitting the sciatic nerve when injecting into the (upper outer quadrant of the) buttocks. The reasoning goes, so long as one is specifically aiming to do a subcutaneous injection, the potentially permanent, paralysing consequences of injecting intramuscular into the sciatic nerve is minimal. Presently, as I am not a doctor, I have not been able to verify if subcutaneous injection is completely without risk of hitting the sciatic nerve in the dorsogluteal region. There are justificatory rumours that prioritising the buttocks over the abdomen may be more optimal for absorption, but I have never found a scientific source implying this, and those more knowledgeable than I have said there is no reason to believe this.

The other school of thought, which I subscribe to, is that risking hitting the sciatic nerve is unacceptable given that the pinching fat in the abdomen and injecting this way not only allows one to see what one is doing but is virtually without any risk comparatively. Notice that literal doctors and nurses can often accidentally hit the sciatic nerve when attempting such injections ¹⁰ . Thighs also bear much less risk, but I will need to research this more.

5.1 What are the general risks of injecting? And how do I inject?

The short answer is that there are very few risks so long as one is injecting subcutaneous into abdomen (thigh is likely as good too, although I have not researched this). So long as one is holding the needle at a right angle to the area of fat pinched (for subcutaneous, see Question 3) and one removes the needle in the same way one inserted it, there should be no risk of the needle bending or breaking inside. There is a minor risk that you are allergic to the castor oil or alternative used in the preparation, so one might want to check this out beforehand, but notice by Question 7 you will only be injecting a little of this anyway. I will research castor oil allergies in case there is potential for severity, but I have never heard of anyone having issues with this.

We will cite this guide on the standard process of injecting subcutaneously. I have not researched risks of subcutaneous injections into abdomens in general, but it does seems as if diabetics tolerate this well long term albeit they may have a risk of Lipohypertrophy . However, notice that this implies this occurs with those who inject daily - you will likely, if you follow this guide, be injecting once a week. Regardless, if patches of hard skin develop lipohypertrophy can be easily ameliorated via changing the injection site each time one injects and exploring other injection sites e.g. if rotating injection site only between the left side of the abdomen and the right side of abdomen causes hard skin to develop, attempt instead left side of abdomen, right side of abdomen, left thigh, right thigh. This purportedly works for diabetic people, who as said previously must inject more often.

5.2 What about the risk of air embolism?

Contrary to one's possible fears, you do not need to worry about air bubbles in your syringe. There is NO risk of air embolism because:

1. You are injecting subcutaneous or intramuscular. It is unlikely you will hit a vein. We will talk about this in Question 5.3.
2. The dosage quantities are far too small. Even if you inject into a vein, air embolism requires at least 20mL of air ¹¹ and the air bubbles in a 1mL syringe will never be this large. You should likely not be injecting more than 0.375mL of a 40mg/mL solution in any case if you are for example ordering from the same supplier I am, and Question 7 will show that the dosage likely can be much lower than this and still suppress testosterone adequately.

5.3 What about the risk of injecting intravenously? Should I always aspirate?

There is no risk at all of injecting intravenously from estradiol itself, because this can be taken intravenously (it is a wasted dose, however, because estradiol will not stay in the blood for long) ¹² . There may be a risk of injecting oils such as castor oil intravenously, but there are reasons for believing that this risk is minimal:

1. The quantity of castor oil etc. should be very low if you are injecting a reasonable (not excessive) amount of estradiol.
2. It is rare to hit a vein in subcutaneous injections to the abdomen. ¹³

I admit however that I aim to research whether or not injecting intravenously with these other ingredients can cause damage, but since in general it appears that intravenous estradiol ester preparations DO NOT differ in studies from subcutaneous it is not that plausible that this would matter ¹² .

With respect to aspirating, the science on aspirating in general as being useful for subcutaneous injections is divided; many claim it is not necessary ¹⁴ , which may render aspiration not worth the discomfort and potential bruising. It is worthwhile to note that diabetics injecting subcutaneous insulin do not in general aspirate (popular auto-injectors obviously do not), and do not seem to have many problems. Again, note that it is 'extremely rare' to hit a vein in subcutaneous injections ¹³ .

6. Which injectable preparation should I use?

It is not known in general which of the main estradiol esters available (valerate/cypionate/enanthate) provides the best feminisation ¹⁵ . I recommend Estradiol Enanthate , if anything at least for the lack of need to inject more than once a week to maintain levels around 200pg/mL This hands-down gives the most steady curves. I am unsure as to whether steady levels are good or even bad for feminisation, but if you have Julia Serano's 'subconscious sex' dysphoria as I do then it may be quite obvious in terms of your mood if your testosterone is no longer suppressed during a trough in blood estradiol curves. Estradiol cypionate does not give as steady curves as enanthate but is still decent, whereas the half-life of Estradiol valerate is much shorter.

Note: Avoid all synthetic estradiols such as ethinyl estradiol, these can have worse adverse side effects such as risk of blood clots, and are not as effective, either. ¹⁶ . In general, stick with the three esters that are most popular (valerate/cypionate/enanthate) because suppliers are obviously more inclined to create these well, and you will not be affected by shortages in a rare type.

7. What dosage should I be using?

CAVEAT: There is huge individudal variability in terms of blood levels following an estradiol injection, see here . The simulator I will now recommend is best paired with likely at least one blood test to make sure estradiol is above 100pg/mL (and not too far above 300pg/mL) and testosterone is below 50ng/dL (see here ).

First investigate the concentration of your estradiol (e.g. 40mg/mL), and also the preparation type (enanathate/cypionate/valerate). If you are injecting 4mg estradiol enanthate every 7 days you will see the following curve on the Transfemscience injection blood levels calculator which appears optimal in the sense of Question 2 and 5 i.e. 200-300pg/mL suppresses testosterone adequately (90%), 300-500pg/mL suppresses to standard cis women ranges (95%) ⁸ , but yet higher levels may suppress breast growth (see Question 2) and also possibly increase risk of blood clots ⁸ . It is also possible that sufficient androgen suppression will occur on levels of 100-200pg/mL for some individuals, but without a blood test it is not possible to know this. If a transfem cannot attain any blood tests at all, I would advise they aim for 200-300pg/mL on the simulator, with the caveat that depending on their individual biology this may substantially vary. See the graphs cited by Transfemscience e.g. this .

Now if you are taking estradiol enanthate, simply calculate how many mL you require to get 4mg estradiol enanthate as 4mg / X mg/mL = Y mL where X is the concentration of your estradiol. For example, if X = 40mg/mL, then you inject 0.1mL every week. If you have instead opted for estradiol cypionate 4mg every 7 days will still suffice, whereas with estradiol valerate the fluctuations will mean you should inject every 4 days at 3mg. That is to say, you should perform the calculation 3mg / Xmg/mL to get the required dose in mL.

¹ . "Clinical studies have found that in men treated with them, estrogens can maximally suppress testosterone levels by about 95% or well into the castrate/female range (< 50 ng/dL)" - Pharmacodynamics of estradiol - Wikipedia , and to verify that the Wikipedia article is reliable notice that it cites studies, this and this

² . See Transfemscience's "Recent Developments on Cyproterone Acetate and Meningioma Risk Out of France and Implications for Transfeminine People"

³ . "However, bicalutamide itself has a small risk of liver as well as lung issues and liver function should be monitored in people taking bicalutamide particularly in the first few months of treatment." - "Information on Bicalutamide (Casodex) as an Antiandrogen for Transfeminine People" , Transfemscience

⁴ "Given that oral estradiol has greater [thromboembolism] risks than non-oral estradiol [...]" - Transfemscience, "An Exploration of Sublingual Estradiol as an Alternative to Oral Estradiol in Transfeminine People" .

⁵ "Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort" - AACE Endocrine Practice, promoted in the unpaywalled "75% of Transgender Women Fail to Suppress Testosterone [on spiro]" . See also Transfemscience's "A Review of Studies on Spironolactone and Testosterone Levels in Cisgender Men and Transfeminine People"

⁶ "These results indicate that estrogen has opposing effects in mammary gland morphogenesis depending on estrogen dose, i.e. low to moderate doses induce terminal end bud formation and ductal elongation while higher doses inhibit these processes [in rodents].", "In vitro studies with human breast epithelial cells as well as other estrogen-target cell lines showed non-monotonic dose–response curves in response to increasing doses of estrogen" - "The mammary gland response to estradiol: Monotonic at the cellular level, non-monotonic at the tissue-level of organization?" - Journal of Steroid Biochemistry & Molecular Biology. See also papers such as "Inhibition of Mammary Growth by Large Amounts of Estrogen", "Mammary Response to Prolonged Estrogenic Stimulation in the Monkey".

⁷ We note that while rodent models have some drawbacks compared to studying non-human primates or even human endocrinology, endocrinology largely is very interested in these models as predictors in general of human response to hormone profiles. See "Modeling menopause: The utility of rodents in translational behavioral endocrinology research" . The fact that in vitro studies also support a non-monotonic dose relationship strengthens this idea ⁶ .

⁸ "More specifically, studies in cisgender men and transfeminine people have found that estradiol levels of around 200 pg/mL (734 pmol/L) generally suppress testosterone levels by about 90% (to ~50 ng/dL [1.7 nmol/L]), while estradiol levels of around 500 pg/mL (1,840 pmol/L) suppress testosterone levels by about 95% on average (to ~20–30 ng/dL [0.7–1.0 nmol/L]) " "An Introduction to Hormone Therapy for Transfeminine People" - Transfemscience . In general Transfemscience warns not to use excessive dosages in case this does affect blood clot risk (95% is adequate testosterone suppression). However it does state the the risks are unknown for injecting estradiol esters ("As with high-dose transdermal estradiol patches, little to no quality data on the risk of blood clots exists for these [injectable] preparations at present." - Estrogens and Their Influences on Coagulation and Risk of Blood Clots"

⁹ "Subcutaneous and intramuscular injection of estradiol cypionate in an aqueous suspension has been found to result in levels of estradiol and other pharmacokinetic parameters (e.g., duration) that were virtually identical" - "Pharmacokinetics of Estradiol" Wikipedia. The source cited is Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg)

¹⁰ See Sciatic nerve injury from intramuscular injection: a persistent and global problem" - Pubmed. I admit that it is more likely with smaller needles one would be injecting subcutaneously, but if one did not have sufficient fat in the area, is the risk not too high given there are safer spots?

¹¹ "In most cases, small amounts of air are broken down in the capillary bed and absorbed into the systemic circulation without any sequelae. To produce symptoms, it is estimated that more than 5 ml/kg of air has to be introduced into the venous system. However, complications can occur with even 20 ml of air.", "Venous Gas Embolism" - StatPearls

¹² "The administration of estradiol valerate by intravenous injection has been studied as well. It has been found to be very rapidly cleaved into estradiol in the blood. The metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection." - "Pharmacokinetics of Estradiol" Wikipedia

¹³ "However, the likelihood of hitting a blood vessel in the subcutaneous fat is extremely rare." - "Is a subcutaneous injection painful?" , Medical News Today

¹⁴ "Aspiration in injections: should we continue or abandon the practice? [version 3; peer review: 2 approved]" - f1000Research

¹⁵ "It is plausible that spikier estradiol concentration–time curves, like with estradiol benzoate, may have overall lower estrogenic potency than more steady curves, like with estradiol enanthate. This is because estrogen receptors for a given tissue should become saturated at a certain point due to the finite quantity of available receptors in the tissue. As a result, high peak estradiol levels with spikier curves may effectively be “wasted” to varying extents in different tissues. On the other hand, more spikey estradiol curves, due to higher peak estradiol levels, might have greater influence on tissues that require high estradiol levels for effect such as the liver (and by extension on coagulation and associated health risks) (Aly W., 2020). However, these possibilities are speculative and thereotical. Although some literature exists that is relevant to this issue (e.g., Parkes, 1937; Bradbury, Long, & Durham, 1953), there is very little research in this area." (I have highlighted the important part in bold) An Informal Meta-Analysis of Estradiol Curves with Injectable Estradiol Preparations Transfemscience

¹⁶ "Non-bioidentical estrogens like ethinylestradiol have greater strength in the liver due to their relative resistance to metabolism and increase blood clot risk more readily than bioidentical estradiol [...]" - "Estrogens and Their Influences on Coagulation and Risk of Blood Clots" Transfemscience