ANGELIQ

17β-estradiol provides hormone replacement during and after the climacteric. The addition of drospirenone opposes the development of endometrial hyperplasia thought to be caused by estrogens. Pharmacodynamics Clinical Pharmacology of Estrogens 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-17β (E2) 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 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues.

Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified.

These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) through a negative feedback mechanism. Estrogen replacement therapy acts to reduce the elevated levels of these hormones seen in postmenopausal women.

Loss of ovarian estradiol-17β production after menopause can result in instability of thermoregulation, causing hot flushes associated with sleep disturbance and excessive sweating. Estrogen replacement therapy is effective in reducing the number and intensity of hot flushes associated with menopause.

Clinical Pharmacology of Progestins Drospirenone (DRSP), a spironolactone analogue, is a progestogen with antimineralocorticoid activity. Similar to spironolactone and endogenous progesterone, drospirenone affects the rennin-angiotensin-aldosterone system (RAAS) by competitive binding to the aldosterone Page 23 of 47 receptor.

As an aldosterone antagonist, drospirenone may retain potassium and cause excess amounts of sodium to be excreted. In animals, drospirenone has no glucocorticoid or antiglucocorticoid activity. Drospirenone is devoid of estrogenic and androgenic activity but is antiandrogenic in animal and in vitro models.

Drospirenone has no effect on glucose tolerance and insulin resistance. In women, glucose tolerance is not compromised by the use of ANGELIQ. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen.

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. The addition of a progestin, in adequate doses and appropriate duration, to an estrogen replacement […]