Estradiol Other names: Oestradiol

The active ingredient, synthetic 17β-oestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

The active ingredient, synthetic 17-beta-estradiol, is chemically and biologically identical to endogenous human estradiol.

Endogenous 17-beta-estradiol induces and maintains the primary and secondary female sexual characteristics. The biological effect of 17-beta-estradiol is carried out through a number of specific oestrogen receptors. The steroid receptor complex is bound to the cells' DNA and induces synthesis of specific proteins.

Maturation of the vaginal epithelium is dependent upon oestrogens. Oestrogens increase the number of superficial and intermediate cells and decrease the number of basal cells in vaginal smear.

Oestrogens maintain vaginal pH around normal range (4.5) which enhances normal bacterial flora.

Treatment of vaginal oestrogen deficiency symptoms: vaginally applied oestrogen alleviates the symptoms of vaginal atrophy due to oestrogen deficiency in postmenopausal women.

A 12-months, double-blind, randomised, parallel group, placebo-controlled, multicentre study was conducted to evaluate the efficacy and safety of estradiol 10 micrograms vaginal tablets in the treatment of postmenopausal vaginal atrophy symptoms.

After 12 weeks of treatment with estradiol 10 micrograms vaginal tablets, the change from baseline, in comparison with placebo treatment, demonstrated significant improvements in the three primary endpoints: Vaginal Maturation Index and Value, normalisation of vaginal pH and relief of the moderate/severe urogenital symptoms considered most bothersome by the subjects.

Endometrial safety of estradiol 10 micrograms vaginal tablets was evaluated in the above mentioned trial and a second, open-label, multicentre trial. In total, 386 women underwent endometrial biopsy at the beginning and at the end of 52 weeks treatment. Incidence rate of hyperplasia and/or carcinoma was 0.52% (95% CI 0.06%, 1.86%), indicating no increased risk.

A 6 week placebo-controlled trial with estradiol 10 micrograms vaginal tablets confirmed significant improvements in Vaginal Maturation Value and normalisation of pH value.

The pharmacokinetic properties of estradiol in humans are well known and depend, in large part, on the extent to which estradiol is taken up by the systemic circulation.

Absorption

Oral administration

Absorption of estradiol is dependent on the particle size: micronized estradiol is rapidly absorbed from the gastrointestinal tract with arithmetic mean T_max values at steady-state of 5.8 hours.

The following table provides the arithmetic mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for 2 mg dose of micronized estradiol. Data is presented as arithmetic mean (standard deviation).

* E1S: data is taken from oral dosing of estradiol 2 mg + dydrogesterone 20 mg (no clinically relevant effects of dydrogesterone on estradiol kinetics are reported).

The extent of systemic absorption of estradiol during treatment with estradiol 10 micrograms vaginal tablets has been evaluated in postmenopausal women aged 49-78 only.

Transdermal administration

Oestrogens are well absorbed through the skin, mucous membranes and the gastrointestinal tract.

Transdermal administration of estradiol achieves therapeutic plasma concentrations using a lower total dose of estradiol than required with oral administration, whereas plasma levels of estrone and estrone conjugates are lower with the transdermal route.

In studies in postmenopausal women with application of estradiol 25, 37.5, 50, and 100 µg/24 hours patches, average peak estradiol serum levels (C_max) were approximately 25 pg/ml, 35 pg/ml, 50-55 pg/ml and 95-105 pg/ml, respectively. Linear pharmacokinetics have been demonstrated for estradiol following transdermal administration.

At steady state, after repeated applications of estradiol 50 µg/24 hours patches, C_max and C_min values were 57 and 28 pg/ml for estradiol and 42 and 31 pg/ml for estrone, respectively.

Vaginal application

After vaginal administration, estradiol is absorbed circumventing first-pass metabolism.

After a brief initial peak, the release of estradiol from vaginal delivery system is constant (7.5 microgram/24 h), for at least 90 days, as governed by Fick’s law of diffusion. As a consequence of the initial release, peak plasma levels of estradiol reach about 55 pg/mL (C_max) within 3 hours (T_max) when the patient applies the first ring to a previously untreated, atrophic vagina. This initial peak dissipates rapidly, and plasma estradiol concentrations return to postmenopausal levels (defined as <20 pg/mL) within 4 hours, and achieve a constant level of approximately 10 pg/mL or less within 2-3 days. This level is maintained for the duration of the 90-day treatment period and is below the serum estradiol levels typically seen with use of transdermal oestrogen therapy (approximately 40 to 70 pg/mL). No data are available on the absolute bioavailability of estradiol from vaginal delivery system.

Distribution

Oestrogens can be found either unbound or bound. About 98-99% of the estradiol dose binds to plasma proteins, from which about 30-52% to albumin and about 46-69% to the sex hormonebinding globulin (SHBG). Only 2% is free and biologically active.

The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. Circulating, unbound oestrogens are known to modulate pharmacological response. Oestrogens circulate in blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugated forms of estradiol and estrone, which undergo rapid interconversion.

Biotransformation

Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the oestrogen activity, either directly or after conversion to estradiol.

Estradiol is metabolised primarily in the liver to estrone, then later to estriol, epioestriol and catechol estrogens, which are then conjugated to sulphates and glucuronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyze the hydroxylation of estradiol forming estriol. Estriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Estradiol metabolites are subject to enterohepatic circulation. The plasma half life of estradiol is 1-2 hours. Metabolic plasma clearance varies between 450-625 ml/min/m². The metabolites are mainly excreted via the kidneys as glucuronides and sulfates. Oestrogens also undergo enterohepatic circulation.

Transdermally applied estradiol is metabolised in the same way as the endogenous hormone.

The vaginal delivery of oestrogens avoids first-pass metabolism and there is limited systemic absorption.

Elimination

The sulphate and glucuronide esters along with a small proportion of estradiol and several other metabolites are excreted in the urine. Only a small amount is excreted in faeces. The elimination half-life of estradiol and its main metabolites is between 10-16 h.

Since estradiol has a short half-life (approximately one hour), serum concentrations of estradiol and estrone returned to baseline values within 24 hours following removal of the patch.

The urinary excretion of total estradiol in the 24-hour urine, 4 and 12 weeks post application of estradiol vaginal ring in a Phase 1 study was 7.23 ± 4.82 nmoles and 8.20 ± 5.45 nmoles, respectively.

Oestrogens are secreted in the milk of nursing mothers.

Linearity/non-linearity

The mean estradiol exposure at steady-state after oral daily dosing of 2 mg micronized estradiol is approximately 2-fold greater than that after daily dosing of 1 mg micronized estradiol. Based on the elimination half-life of the micronized estradiol, it can be estimated that estradiol concentrations reach steady-state approximately within one week following oral daily administration.

Estradiol follows apparent linear kinetics for systemic concentrations up to 550 pmoles/L following administration of vaginal ring containing doses of 2 to 400 mg.

The toxicity profile of estradiol has been well established. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver as well as the frequency of lymphoid and pituitary tumours.