ESTRADIOL GEL 0.1%

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date

Contraindications

• • or history of these conditions [see Warning and Precautions ( 5.1 )] Active arterial thromboembolic disease (for example
• • stroke or MI)
• • or a history of these conditions [see Warning and Precautions ( 5.1 )] Known anaphylactic reaction
• • angioedema
• • or hypersensitivity to estradiol gel 0.1% Hepatic impairment or disease [see Warnings and Precautions ( 5.9 )] Protein C