Estradiol can be taken by a variety of different
routes of administration. Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle are in the range of 80 to 150 pg/mL, according to some sources. In postmenopausal women, circulating levels of estradiol are below 15 pg/mL. Estradiol levels range from 1,000 to 40,000 pg/mL across pregnancy, are on average 25,000 pg/mL at term, and reach levels as high as 75,000 pg/mL in some women.
Oral administration Absorption and bioavailability The oral
bioavailability of estradiol is very low. This is due to the fact that estradiol is poorly
soluble in water, which limits its
dissolution and
absorption, and is additionally subject to extensive
metabolism during the
first pass through the
intestines and
liver. All oral formulations of estradiol available today are micronized, Oral non-micronized estradiol and oral micronized estradiol do not appear to have ever been directly compared in a study. Both have been assessed independently however, and have been found to produce significant estrogenic effects. In accordance, studies of the amount of oral estradiol necessary for
endometrial proliferation in women have reported a total dose of 60 mg for micronized estradiol relative to 120 to 300 mg or more for non-micronized estradiol. As such, micronization has been said to substantially improve the potency of oral estradiol. A preparation with the smallest particles (mainly
Transdermal gel with a prescription Estradiol is available as a transdermal gel in the form of gel dispensers and gel packets. Major estradiol gel dispenser products include EstroGel and Elestrin while major estradiol gel packet products include DiviGel and Sandrena. Estradiol gels are administered daily. The time-averaged levels of circulating estradiol and estrone with this formulation over the 24-hour dose interval were 28.3 pg/mL and 48.6 pg/mL, respectively. Transdermal estradiol gel produces an estradiol to estrone ratio of about 1:1. In these studies, levels of estradiol with estradiol gel or ointment were 84 pg/mL with 3 mg/day, 185 pg/mL with 6 mg/day, 107 pg/mL with 10 mg/day, and 473 pg/mL with 20 mg/day. Studies have found that topical application of estradiol to the breasts increases local levels of estradiol in breast tissue. The total
endometrial proliferation dose of transdermal estradiol gel in women has been reported to be 150 mg per cycle or 14 days.
Other transdermal formulations Estradiol is available in the form of transdermal
emulsions (e.g., Estrasorb) and
sprays (e.g., Lenzetto, Evamist). Vaginal estradiol is rapidly and almost completely
absorbed. On the other hand, a first pass effect in the uterus may occur with vaginal administration of estradiol and this may have implications for uterine safety.
Rectal administration and hence the
first-pass metabolism that occurs with oral estradiol, similarly to other parenteral routes of estradiol such as vaginal and transdermal administration.
Irritation of the
intestines does not usually occur with rectal estradiol. Administration of a rectal
suppository containing 100 mg estriol resulted in estriol levels in
pregnant women
at term increasing by about 53%.
Intramuscular injection Intramuscular injections are
injections into
muscle, for instance the
gluteal or
deltoid muscle. Estradiol and
estradiol esters can be administered in a variety of forms by intramuscular injection.
Aqueous solutions of estradiol and estradiol esters by intramuscular injection have a rapid
onset and
duration analogously to but slightly more delayed than
intravenous injection. However, intramuscular injections of
oil solutions,
crystalline aqueous suspensions, and
emulsions of estradiol and estradiol esters, as well as solutions and suspensions of estradiol
polymers and estradiol
microspheres, act as long-lasting
depot injections. Estradiol esters, including but not limited to
estradiol benzoate,
estradiol valerate,
estradiol cypionate,
estradiol enanthate, and
estradiol undecylate, are inactive
prodrugs of estradiol that are converted into estradiol in the body. The aforementioned estradiol esters are
fatty acid esters and are more
lipophilic (fat-soluble) than estradiol. More lipophilic compounds are absorbed more slowly from the injection site when given by depot intramuscular injection (as oil solutions, aqueous suspensions, and emulsions), and hence more lipophilic estradiol esters have longer durations than free estradiol or less lipophilic estradiol esters via this route.
Polyestradiol phosphate is a polymer of the
hydrophilic (water-soluble) estradiol ester
estradiol phosphate which circulates in the blood but is metabolized into estradiol very slowly. The
bioavailability of estradiol and estradiol esters given by intramuscular injection is said to be essentially complete. A single 1 to 2 mg dose of estradiol in oil solution by intramuscular injection has a duration of about 1 or 2 days. Little prolongation of duration is achieved with the use of larger doses. Nonetheless, the duration of estradiol in oil solution by intramuscular injection is significantly longer than an
intravenous injection of estradiol or
estradiol valerate, which show a duration of only a few hours. Conversely, intramuscular injections of estradiol esters in oil solution have durations of days to months, depending on the ester administered. The durations with a 5 mg dose are 4 or 5 days with estradiol benzoate, 7 or 8 days with estradiol valerate, and 11 to 14 days with estradiol cypionate. With estradiol valerate, it is reported that a dose of 5 mg has a duration of 7 to 8 days, A study of
pseudopregnancy with intramuscular injections of 40 mg/week estradiol valerate and 250 mg/week
hydroxyprogesterone caproate observed estradiol levels of about 2,500 to 3,000 pg/mL. It was used at a dose of 0.5 to 1.5 mg 2 or 3 times per week. As such, the preparation presumably had a duration in the range of 2 to 7 days. have been found to have longer
duration of actions than oil solutions of the same esters when administered via intramuscular injection. Whereas the duration of a single intramuscular injection of
amorphous estradiol benzoate in oil solution is 6 days, the duration of a single intramuscular injection of microcrystalline estradiol benzoate in aqueous suspension is 16 to 21 days. The duration of crystalline aqueous suspensions is highly dependent on
crystal size.
Steroids and steroid
fatty acid esters are
lipophilic and have very low
water solubility. When they are suspended in the form of crystals in water, these crystals dissolve slowly, releasing steroid from their surfaces in the process. The larger the
particle sizes of the crystals, the slower the dissolution rate. A larger
needle size is needed for aqueous suspensions of steroids to allow the steroid crystals to pass through the needle lumen. Aqueous suspensions pose a risk of
injection site reactions such as local
irritation,
swelling, and
redness, with often severe pain. Particle sizes of more than 300 μm in the case of estradiol benzoate have been found to be too painful for use.
Emulsions Emulsions are
mixtures of
immiscible liquids.
Water-in-oil emulsions of estradiol benzoate were evaluated as long-acting preparations for use by intramuscular injection in the 1940s and 1950s. A 10 mg dose of estradiol benzoate in emulsion by intramuscular injection is said to have a duration of about 2 to 3 weeks.
Polymers Polymers are large molecules of
repeating subunits.
Polyestradiol phosphate (brand name Estradurin) is a
water-soluble estradiol ester in the form of a
polymer and a very slowly hydrolyzed prodrug of estradiol. It is formulated as an
aqueous solution and is given by intramuscular injection. Estradiol levels during polyestradiol phosphate therapy are very constant and uniform.
Microspheres Microspheres are microscopic spherical particles which can be used to
encapsulate compounds. Estradiol is available in the form of an
aqueous suspension of 1.0 mg estradiol in microspheres for use by intramuscular injection once a month under the brand name Juvenum E in
Mexico. It achieves circulating estradiol levels of 163 pg/mL to 219 pg/mL in the first 3 to 12 hours following injection, which decrease to 42 to 66 pg/mL during the first 4 days post-injection and to 20 to 35 pg/mL after 8 days, with levels remaining in this range thereafter over 30 days. 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. In addition, studies have found that many intramuscular injections are really subcutaneous injections, as individuals often do not actually penetrate deep enough to inject into muscle when attempting to perform an intramuscular injection and instead inject into the subcutaneous fat layer above the muscle. This is particularly prevalent with injections into the
buttocks and in
overweight and
obese individuals, due to the thicker layer of fat over muscle. These pellets slowly and completely dissolve and are replaced once every 6 to 12 months, achieving high and very constant circulating levels of estradiol. They are
surgically inserted with the aid of a
trocar by a trained physician in a medical office or clinic, and can be placed into locations including the lower
abdomen, lower
back,
buttocks, or
hips. Pharmaceutical estradiol pellet implants have been used almost exclusively in the
United Kingdom, but have also been available in
Australia and the
Netherlands. However, estradiol pellets have been discontinued in both the United Kingdom and Australia. An estradiol implant has not been approved by the FDA as a pharmaceutical medication in the United States, but hormone pellet implants, including estradiol pellets, are available as custom
compounded products in this country. Estradiol pellet implants are advantageous in that some women seem to need higher levels of estradiol for adequate relief of menopausal symptoms, and subcutaneous estradiol pellets are easily able to achieve such levels. When recurrence of hot flashes occurs with estradiol pellets, treated women often complain that their pellet has "run out".
Intrauterine administration Intrauterine estradiol has been studied in the treatment of
uterine hypoplasia in women. It has been found to be very rapidly cleaved into estradiol in the blood. Both of these medications act in part as
prodrugs of estradiol. The formulation is given in a single injection but can be repeated after 6 to 12 hours if necessary. Estramustine phosphate was initially introduced as an intravenous formulation and was only later introduced as an oral medication. ==General==