Oestrogel Mechanism of Action

Pharmacotherapeutic group: ESTROGENS (genito-urinary system and sexual hormones). ATC classification: G03CA03.
Pharmacology: Pharmacodynamics: Estradiol gel belongs to the group of natural, physiological estrogens. The active ingredient is chemically and biologically identical to human endogen estradiol. The pharmaceutical form enables the systemic administration of 17β-estradiol by applying it to healthy skin. Estradiol gel substitutes for the loss of estrogens production in post-menopausal or ovariectomised women.
The most active form of estrogens is estradiol which is mainly produced by the ovarian follicles throughout the child-bearing period of women's life.
The transdermal administration of Estradiol gel enables to avoid the hepatic first pass effect which induces an increase in the synthesis of angiotensin, VLDL lipoproteins (triglycerides) and certain coagulation factors.
Pharmacokinetics: Pharmacokinetic studies indicate that, when applied topically to a large area of skin in a volatile solvent, approximately 10% of the estradiol is percutaneously absorbed into the vascular system, regardless of the age of the patient. Daily application of 2.5g or 5g Oestrogel over a surface area of 400-750cm² results in a gradual increase in Estrogen blood levels to steady state after approximately 3-5 days and provides circulating levels of both estradiol and estrone equivalent in absolute concentrations and in their respective ratio to those obtained during the early-mid follicular phase of the menstrual cycle.
Oestrogel was administered to 17 postmenopausal women once daily on the posterior surface of one arm from wrist to shoulder for 14 consecutive days.
Maximum serum concentrations (C_max) of estradiol and estrone on Day 12 were 117 pg/ml and 128 pg/ml, respectively.
The time-averaged serum estradiol and estrone concentrations (C_average) over the 24 hour dose interval after administration of 2.5 g of Oestrogel on Day 12 were 76.8 pg/ml and 95.7 pg/ml, respectively.
Metabolism of estradiol takes place mainly in the liver under oestriol, estrone and their conjugated metabolites (glucuronides, sulphates). These metabolites also undergo enterohepatic recirculation.
When treatment is stopped, estradiol and urinary conjugated estradiol concentrations return to baseline in about 76 hours.
Toxicology: Preclinical safety data: Long-term continuous administration of estrogen, with and progestin, in women, with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer.
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.