Source: Health Products and Food Branch (CA) Revision Year: 2016
Estrogen drug products act by regulating the transcription of a limited number of genes. They may act directly at the cell’s surface via a non “estrogen receptor” mechanism or directly with the estrogen receptor inside the cell. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in the wall of blood vessels, in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.
Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Along with other hormones such as progesterone, estrogens are intricately involved in the process of menstruation. Estrogens also affect the release of pituitary gonadotropins. A depletion of endogenous estrogens occurs postmenopausally as a result of a decline in ovarian function, and may cause symptomatic vulvovaginal atrophy.
Estrone is water soluble and can be readily absorbed into the blood stream through skin and mucous membranes.
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are distributed in the body and generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Absorbed hormone is metabolized by the liver much the same as endogenous hormone. Complex metabolic processes create a dynamic equilibrium of inter conversion between estrone and estradiol and between esterified and non esterified forms.
Estrogen administered intravaginally is not subject to true “first-pass” metabolism, but will undergo hepatic uptake, metabolism, and enterohepatic recycling. Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; but, they are re-absorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favour excretion through the kidneys since tubular re-absorption is minimal.
A portion of the estrogen is excreted into the bile to be reabsorbed via the intestine and back to the liver. During the course of enterohepatic recirculation, estrogens are desulfated and resulfated, undergo degradation to less active estrogens such as estriol, are oxidized to nonestrogenic substances which interact with catecholamine metabolism and are conjugated with glucuronic acids to be excreted in the urine.
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
There are 3 main estrogens found in the human body they being 17β-estradiol, estrone and estriol. Estradiol the most potent is produced by the ovarian follicle during child bearing years. However at menopause most estrogen is derived from the conversion of androstenedione to estrone by peripheral tissues. In the case for estrone in a vaginal cream the estrogen is present to bind to the receptors of estrogen responsive tissue that line the vagina.
Although the amount of estrone available per treatment is low, the concomitant use of a progestin is a necessary precaution to protect against endometrial hyperplasia in women with intact uteri.
See Actions and Clinical Pharmacology section under Part I.
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.
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