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Estradiol Valerate versus Estradiol Cypionate: Dosage and Potency

By Aly W. | First published December 21, 2018 | Last modified October 5, 2020


This is an old Reddit comment I wrote from elsewhere in response to a person asking about the recommended dosages for estradiol valerate and estradiol cypionate I chose for my introduction to hormone therapy for transfeminine people. It concerns the dosage and potency of estradiol valerate versus estradiol cypionate both by intramuscular injection. Specifically, there is a popular notion that an equal dose of estradiol cypionate is stronger or more potent than estradiol valerate. There is no basis for this notion however, so I decided to thoroughly debunk it in my comment. I thought that I would post it as a page here for easier access and wider viewing. Here’s my comment:


I am confident that the dosage of estradiol cypionate is correct. I’ve given it careful consideration. Estradiol esters have approximately 100% bioavailability by intramuscular or subcutaneous injection, and after taking into account/controlling for the differences in molecular weight caused by the varying esters used, estradiol esters are essentially equipotent. The longer elimination half-life is a little bit misleading because it’s different than the typical case of a drug half-life in pharmacology. Estradiol esters form a local depot in muscle and fat when they’re injected, and they’re slowly released from this depot. The rate of release differs based on the lipophilicity of the ester, which in turn is related to its chain length (longer chain, more lipophilic, slower release). This rate of release is the critical factor in the overall elimination half-life of the estradiol ester. Once the estradiol ester has been released from the local tissue depot, it is rapidly cleaved into estradiol and the ester (e.g., cypionic acid) and hence has a short terminal half-life. So essentially estradiol esters have very long absorption half-lives (t1/2α) (days, weeks, or months) but very short terminal half-lives (t1/2β) (minutes or hours). As such, unlike with the elimination half-lives of most drugs (e.g., bicalutamide), in which there is a short absorption half-life and a long terminal half-life, a longer elimination half-life of an estradiol ester doesn’t result in greater total estradiol exposure compared to another estradiol ester with a shorter elimination half-life.

Take a look at the curves here and here. The areas under the curves (total estradiol exposure) are slightly different among the different esters because of differences in molecular weight due to the different esters used (benzoic acid, cypionic acid, valeric acid, heptanoic acid). But as you can see, despite the same doses being used (except a double dose in the case of estradiol enanthate), the areas under the curves and hence total estradiol exposures are similar. In general, estradiol esters with shorter ester chains have longer durations but lower estradiol levels while estradiol esters with longer ester chains have shorter durations but higher estradiol levels.

I disagree with the recommended estradiol ester dosages in the UCSF guidelines. They’re likely based on precedent but aren’t really accurate to the available clinical evidence. The recommendations of 20 to 40 mg estradiol valerate once every two weeks and 2 to 5 mg estradiol cypionate once every two weeks are extremely disproportionate in terms of total estradiol exposure (around 10-fold) and don’t make much sense. The strange recommended doses may originate from the fact that the United States Food and Drug Administration (FDA) has approved intramuscular estradiol valerate at doses of 10 to 20 mg every four weeks for menopausal symptoms (FDA) while intramuscular estradiol cypionate is approved at doses of 1 to 5 mg every three to four weeks for menopausal symptoms (FDA). Why this is the case, I’m not sure. However, it might have to do with the fact that long ago in the past, very high doses of estrogens were used with little thought, whereas later on, after health concerns relating to cardiovascular toxicity, venous thromboembolism, and endometrial cancer initially emerged in the 1960s and 1970s, estrogen doses were greatly reduced and the lowest possible doses came to be preferred. This is notable because, whereas the currently available formulations of intramuscular estradiol valerate were first approved by the FDA in 1954 (FDA), the currently available formulations of intramuscular estradiol cypionate were approved in 1979 (FDA). In any case, regardless of the reason as to why, the different dosages of intramuscular estradiol valerate and intramuscular estradiol cypionate approved by the FDA for the treatment of menopausal symptoms have led to a popular false perception that estradiol cypionate is considerably more potent than estradiol valerate.

An alternative or additional possibility for the different FDA-approved dosages is that intramuscular estradiol cypionate has a longer duration than intramuscular estradiol valerate and so higher doses of estradiol valerate may be needed to prolong its duration and allow for a similar once-monthly dosing interval for menopausal symptoms. The dosages are much too disproportionate (and the elimination half-lives not different enough) for this to be a sole explanation though.

Whatever the case may be, we know that the perception that intramuscular estradiol cypionate is more potent than intramuscular estradiol valerate is false, besides the clear pharmacokinetic evidence (estradiol curves for intramuscular estradiol valerate and estradiol cypionate), because the World Health Organization extensively studied the pharmacology of intramuscular estradiol valerate and estradiol cypionate in the 1980s and 1990s as part of their Special Programme for developing new methods of birth control (Wiki; Review; Review). They developed estradiol valerate and estradiol cypionate as the estrogen components in long-lasting once-monthly combined injectable contraceptives, and determined a 5-mg dose to be appropriate for both estradiol esters (Wiki). These forms of birth control have been approved and marketed widely throughout the world, including previously in the United States (an estradiol cypionate-containing product was discontinued in 2003 due to poor sales). The reviews that have been published on combined injectable contraceptives go in-depth into their pharmacology and clearly demonstrate the approximate equipotency of 5 mg intramuscular estradiol valerate and 5 mg intramuscular estradiol cypionate on a variety of different clinical measures of estrogenicity.

Personally, I think that the recommended dosing regimens of intramuscular estradiol valerate in the UCSF guidelines are not well-formulated at all. The single doses are far too high, and I think that a two-week dosing interval is not ideal in the case of estradiol valerate due to its relatively short elimination half-life. Levels of estradiol are going to fluctuate profoundly with such doses and with a two-week dosing interval, spiking extremely high and then dropping quite low. Conversely, I think that the intramuscular estradiol cypionate dosages are much too low and I think that a two-week dosing interval may not be ideal in the case of estradiol cypionate either. I believe that a 5- to 7-day dosing interval for intramuscular estradiol valerate and a 7-day interval for intramuscular estradiol cypionate may be best, at least in pursuance of a goal of maintaining steady estradiol levels. I base my opinions primarily on maintenance of the estradiol levels required for proper suppression of testosterone levels in pre-op/non-op transgender women, and also on avoiding any potential hypothetical estradiol-induced gonadotropin and testosterone surges that might be triggered by dosing intervals that are too widely spaced (Reddit).

Update 1

I wanted to also address another point. Some have speculated that estradiol cypionate is more potent than estradiol valerate and that this accounts for the different dosage recommendations. This is claimed to be because estradiol levels with estradiol valerate spike much more sharply than with estradiol cypionate, the estrogen receptors are saturated during this spike, and consequently much of the estradiol is “wasted”. However, there is no evidence to support this hypothesis, and it notably does not match up with the literature. See the following tables on estrogen dosage recommendations from books published in the 1970s and 1980s:

Table: Drugs Used in the Treatment of Hormonal Disorders: Estrogens (Trounce, 1970; Trounce, 1976):

Estrogen“Usual dose”Route
Estradiol benzoate1–5 mg 1–3x/weekIM injection
Estradiol cypionate1–5 mg 1x/3–4 weeksIM injection
Estradiol dipropionate1–5 mg 1x/weekIM injection
Estradiol valerate5–20 mg 1x/2–4 weeksIM injection

Table: Estrogenic Drugs Used in Replacement Therapy (Thomas & Keenan, 1986):

Estrogen“Dose for replacement therapy”Route
Estradiol benzoate0.5–1.5 mg 2–3x/weekIM injection
Estradiol cypionate1–5 mg 1x/weekIM injection
Estradiol valerate10–40 mg 1x/1–4 weeksIM injection

Notice how the recommended doses for the different parenteral estradiol esters, aside from being somewhat all over the place and not necessarily corresponding to one another, are very different for estradiol valerate compared to all the other esters. Estradiol valerate is the only one in which high single doses (5 to 40 mg) are recommended, whereas the recommended single doses are much lower for all of the other estradiol esters (0.5 to 5 mg). This is notably regardless of the duration of the ester—estradiol benzoate and estradiol dipropionate both have shorter durations than estradiol valerate, but estradiol cypionate has a longer duration than estradiol valerate. To me, this suggests that the doses and dose intervals were probably arbitrary. Moreover, I think that the above could be interpreted as supporting the notion that higher single doses of estradiol valerate were recommended to allow for an extended duration relative to what would have been the case otherwise. A single injection of a large dose of estradiol valerate could potentially produce effects for a month, whereas a single low dose would have a much shorter duration.

Update 2

See also the discussion here for additional information.