By Aly W. | First published December 21, 2018 | Last modified August 6, 2021
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 reliable 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.
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 (Wiki).
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:
|Estradiol benzoate||1–5 mg 1–3x/week||IM injection|
|Estradiol cypionate||1–5 mg 1x/3–4 weeks||IM injection|
|Estradiol dipropionate||1–5 mg 1x/week||IM injection|
|Estradiol valerate||5–20 mg 1x/2–4 weeks||IM injection|
Table: Estrogenic Drugs Used in Replacement Therapy (Thomas & Keenan, 1986):
|Estrogen||“Dose for replacement therapy”||Route|
|Estradiol benzoate||0.5–1.5 mg 2–3x/week||IM injection|
|Estradiol cypionate||1–5 mg 1x/week||IM injection|
|Estradiol valerate||10–40 mg 1x/1–4 weeks||IM 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.
Some additional discussion which has been adapted here:
[EC and EV] are not 1:1 [in dose/potency], not even close, more like 10:1. See the link I provided; starting dose for EV is 20mg/2w while starting dose for EC is 2mg/2w.
Also, per the UCSF guidelines I cited, the difference is as stark as I claimed; so I’m being factually accurate.
I believe that the UCSF guidelines and Deutsch are mistaken on this issue. Many other sources have recommendations that are at odds with those of the UCSF guidelines. For instance, the Endocrine Society recommends the same dosages for both estradiol valerate and estradiol cypionate in their 2009 and 2017 guidelines (Hembree et al., 2009; Hembree et al., 2009). The Endocrine Society’s guidelines are generally considered to be the most credible guidelines for transgender hormone therapy. Similarly, various literature reviews list estradiol valerate and estradiol cypionate dosages as either the same or similar (Fabris, Bernardi, & Trombetta, 2015; Randolph, 2018; Tangpricha & den Heijer, 2017; Meriggiola & Gava, 2015; Nakatsuka, 2010).
As I described in the article I linked, similar potencies of estradiol valerate and estradiol cypionate were thoroughly established during the development of combined injectable contraceptives. The World Health Organization spent decades studying and developing these formulations. See these literature excerpts (Said et al., 1988; Sang, 1994; Benagiano et al., 2012; Runnebaum, Rabe, & Kiesel, 1988):
In response to the demand from certain populations for safe, well-investigated, once-a-month injectable contraceptives with high efficacy and giving minimal disruption of menstrual bleeding, the World Health Organization’s Special Programme of Research in Human Reproduction devised a strategy for the development of once-a-month contraceptives. This involved, as an initial phase, the optimization of the dosage and progestogen:estrogen ratio of two combination formulations based on DMPA and estradiol cypionate and NET-EN and estradiol valerate. Studies on the pharmacokinetic profiles and pharmacodynamic effects of the estrogens alone (6) and of various dosage combinations of the progestogens and the estrogens have shown the optimal dosages and progestogen:estrogen ratios to be NET-EN, 50 mg plus estradiol valerate, 5 mg (HRP102) and DMPA, 25 mg plus estradiol cypionate, 5 mg (HRP 112) (7, 8, 9).
Pharmacokinetic/pharmacodynamic study on estrogenic components suggested that estradiol valerate and cypionate were suitable estrogen esters to give elevated plasma estrogen levels for 7 to 11 days. After a single injection of Cyclofem and Mesigyna, both formulations showed equal contraceptive effect with inhibition of follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days. Multicentre studies on the optimization of dosages of progestogens and estrogens in once-a-month injectables confirmed that the full doses of Cyclofem (DMPA 25 mg/estradiol cypionate 5 mg) and Mesigyna (NET-EN 50 mg/estradiol valerate 5 mg) are suitable for large scale clinical trials. Pharmacodynamics and progestogen/estrogen ratio study indicated the importance of not only the absolute amounts of the progestogen and estrogen but also of their ratio. Reduction of estrogen dose resulted in breakthrough ovulation with both Cyclofem and Mesigyna.
Regarding the choice of estrogen component for the monthly injectables, estradiol valerate has the most appropriate pharmacokinetic profile, which should be a rapid rise in circulating estrogen levels, reaching a peak in about 2 days and declining to zero about 14 days after the intramuscular administration of 5 mg estradiol valerate in arachis oil. The administration of estradiol cypionate gave significantly lower peak levels of estradiol and estrone than that of estradiol valerate. The average duration of elevated estrogen levels was 4 to 5 days with the administration of estradiol benzoate, which was shorter than estradiol valerate.27
To allow the optimization of dosage of NET-EN/estradiol valerate and DMPA/estradiol cypionate combinations, a series of pharmacokinetic/pharmacodynamic studies was completed by WHO. From a detailed comparative pharmacokinetic/pharmacodynamic study of Cyclofem and Mesigyna, it was suggested that both monthly injectables are capable of inhibiting follicle maturation for some 30 days and ovulation, corpus luteum formation for some 60 days.31 These two combinations provide a considerable margin of safety in terms of the expected duration of contraceptive protection. […] Levels of estradiol equivalent to a pre-ovulatory estradiol peak were seen with both estrogen esters, being higher with the valerate than the cypionate, and estradiol levels returned to baseline before the end of each treatment cycle. Each injection of both monthly injectables was followed by a bleeding-free period of approximately two weeks, and gave good bleeding patterns. […]
Development of Monthly Oestrogen-Progestin Combinations
The main reasons women discontinue use of progestin-only injectable contraceptives such as DMPA are menstrual disturbances, in particular heavy bleeding, irregular, unpredictable bleeding and amenorrhoea. In the 1970s, to offer women an alternative, HRP undertook a review of all available combined, monthly preparations and decided to optimize the dosage and the progestin/oestrogen ratio of two products, Cyclofem and Mesigyna, and to oversee their clinical evaluation.
Early dose-finding studies  showed that effectiveness would decrease with a low progestin/oestrogen ratio, while cycle control would decrease if this ratio was too high. Thus the optimal compositions were found to be 25 mg DMPA plus 5 mg oestradiol cypionate for Cyclofem, and 50 mg NET-EN plus 5 mg oestradiol valerate for Mesigyna. Subsequent pharmacokinetic, pharmacodynamic [57, 58] and metabolic studies [59–61] and clinical trials [62–67] established the efficacy and safety of both preparations. Introductory studies followed in a number of countries [68, 69] , illustrating a variety of experiences and service delivery issues.
Currently, each preparation is registered in over 35 countries and an estimated 8 million women use a once-a-month injectable preparation.
Various injectable steroid contraceptives with a duration of action ranging from 1 to 6 months have been analyzed. Some new steroid formulations providing contraceptive protection for more than 2 months are in an early phase of development, and two once-a-month injectables with HRP 102 and HRP 112 have been studied intensively. Recent results indicate that the dosages of the two once-a-month injectables (HRP 102 and HRP 112), which are now in phase III of clinical trials (50 mg norethisterone enanthate and 5 mg estradiol valerate in HRP 102;  mg Depo-medroxyprogesterone acetate and 5 mg estradiol cypionate in HRP 112), seem to be optimal.
Earlier results from the phase III clinical trial in 17 centres covered more than 2300 patients. The withdrawal rate due to disturbed menstrual bleeding after 12 months was 6.4% for HRP 112 and 7.4% for HRP 102 (compared to 14%–15% in patients treated with Depo-medroxyprogesterone acetate and norethisterone enanthate).
As alluded to above, EV/NET-EN and EC/MPA (both 5 mg of estradiol ester) have been directly compared as combined injectable contraceptives in multiple large clinical trials (Newton, d’Arcangues, & Hall, 1994). For instance, in the phase III study consisting of 2,328 women in 12 countries described just above (Said et al., 1988; WHO et al., 1989).
All of this of course accords with the fact that area-under-the-curve estradiol levels are similar with equal doses of estradiol valerate and estradiol cypionate, per the curves I linked earlier. Although there are small differences in molecular weight between them due to the different esters that are attached (Wiki-Table), as well as differences in peak estradiol levels and total duration of estradiol release, it would appear that estradiol cypionate and estradiol valerate are essentially around 1:1 in terms of overall estrogenic exposure and potency. And definitely not 10:1.
Taken together, the evidence isn’t in favor of Deutsch’s dosage recommendations. Nor of the notion that estradiol valerate and estradiol cypionate differ considerably (if at all) in potency.
Yes, the different rates of estradiol release with estradiol valerate vs. estradiol cypionate, and hence the differing estradiol levels at single points in time (e.g., peak), complicate the situation. Estradiol valerate may achieve around 2-fold higher peak estradiol levels than estradiol cypionate (Wiki-Graph), for instance, but at the same time, as you mention, result in estradiol levels returning more quickly to baseline/trough (e.g., 7–8 days for 5 mg estradiol valerate, 11–14 days for 5 mg estradiol cypionate—Wiki-Table).
Obviously estrogenic responses at peak following a single injection are going to be stronger with 2-fold higher estradiol levels. And estrogenic signaling will, of course, be weaker with 5 mg estradiol valerate relative to 5 mg estradiol cypionate at say 8 days post-injection, when estradiol valerate is pretty much spent but estradiol cypionate is still releasing estradiol (3-fold higher levels at this point still).
Things balance out with continuous weekly injections due to carryover in estradiol levels with estradiol cypionate however. Not perfectly or completely of course. There will always be more variation in estradiol levels with estradiol valerate relative to estradiol cypionate. But certainly to a considerable degree in any case. And one that, in my opinion, allows 1:1 overall potency to be an accurate and valid simplification. (Not even taking into consideration area-under-the-curve estradiol levels at this point.)
My saying “essentially 1:1” was mainly to contrast with and help debunk the 10:1 claim, which was my more important point. I think I’ve succeeded in debunking the 10:1 notion.