Estrogens

• 1: Transdermal gel and patches
• 2: Oral
• 3: Injections
• 4: Pellets
• 5: Sources on the risks of thrombosis

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.

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 - 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.

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.

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