In vivo estrogens diffuse through cell membranes, distribute throughout the cell, bind to and activate the estrogen receptors, thereby eliciting their biological effects. Estrogen receptors have been identified in tissue of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. The estrogen contained in VAGIFEM, 17 β-estradi-ol is chemically and biologically identical to the endogenous human 17 β-estradiol and is, therefore, classified as a human estrogen.

Estrogens regulate growth, differentiation and functioning of many different tissues within and outside of the reproductive system. Estrogens are intricately involved with other hormones, especially progesterone, and during the ovulatory phase of the menstrual cycle cause proliferation of the endometrium. Most of the activity of estrogens appear to be exerted via estrogen receptors in target cells of tissues of the woman's reproductive tract: breast, pituitary, hypothalamus, brain, liver, and bone. The steroid-receptor complex is bound to the cell's DNA and induces synthesis of specific proteins. Maturation of the vaginal epithelium is dependent on estrogen as it increases the number of superficial and intermediate cells as compared with basal cells. Estrogen keeps the pH of the vagina at approximately 4.5 which enhances normal bacterial flora, predominately, Lactobacillus döderlein.

Pharmacokinetics

Absorption

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

A single-center, randomized, double-blind comparison study conducted in the U.S. showed that vaginal application of VAGIFEM® over a 12-week course demonstrated a mean Cmax of estradiol of 50 pg/mL and that there was no significant accumulation of estradiol as measured by the AUC_0-24 (See Table 1 below).

Table 1: MEAN (±STANDARD DEVIATION) PHARMACOKINETIC PARAMETERS FOR ESTRADIOL (Uncorrected for base line) Timepoint

Distribution

Circulating, unbound estrogens are known to modulate pharmacological response. Estrogens circulate in the blood bound to sex-hormone binding globulin (SHBG) and albumin. A dynamic equilibrium exists between the conjugated and the unconjugat-ed forms of estradiol and estrone, which undergo rapid interconversion.

Metabolism

Exogenously-delivered or endogenously-derived estrogens are primarily metabolized in the liver to estrone and estriol, which are also found in the systemic circulation. VAGIFEM intravaginal administration avoids first-pass metabolism thatoccurs withoralestrogens.

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