Femtrace™
Classification:
Genitourinary Agents
Hormones and Hormone Modifiers
NOTE: Several different estrogens are commercially available as single agents. Separate monographs appear for conjugated estrogens, esterified estrogens, and the individual estrogen-progestin combinations.
Description: Estradiol is the principal intracellular human estrogen and is substantially more active than its metabolites, estrone and estriol, at the cellular level. Estradiol can be obtained from natural sources or prepared synthetically into a variety of salt forms. Due to almost complete first-pass metabolism, estradiol must be given in a micronized oral dosage form to ensure therapeutic effect. Esterification of estradiol to estradiol cypionate or valerate increases the parenteral duration of action of estradiol to allow for IM administration. Estradiol is used to prevent osteoporosis and relieve symptoms associated with menopause and is also used to treat female hypogonadism and other abnormalities of female gonadotropin dysfunction. In selected circumstances, estrogens have been used to treat advanced inoperable breast carcinoma in both sexes or prostatic carcinoma. The FDA began approving various estrogen products in 1938, its first year of organization. Estradiol is available in several unique delivery systems. In addition to oral tablets, estradiol is available as topical patches, emulsions, and gels; intravaginal creams, tablets, and rings; and parenteral injections. The estradiol vaginal ring, Femring™, was approved by the FDA in March 2003. Estrasorb™ (topical estradiol emulsion) received FDA approval in October 2003, while EstroGel® (topical estradiol gel) received FDA approval in February 2004. Menostar™, a lower-dose estradiol patch for osteoporosis prevention, was FDA approved in June 2004.
Chemical Structure(s) For: Estradiol
In regard to the use of estrogen for hormone replacement therapy (HRT), unopposed estrogen has been associated with increased risk of endometrial cancer in women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. However, combination HRT therapy may add additional health risks for some women, as evidenced by the HERS trials, the Women’s Health Initiative study, and other investigations. In particular, because the Women’s Health Initiative (WHI) study reported an increased risk of myocardial infarction, stroke, invasive breast cancer, and venous thromboembolism, experts generally concur that patients should be prescribed estrogen HRT or estrogen-progestin HRT for the shortest duration consistent with the treatment goals. Estrogen HRT, with or without a progestin, is not indicated and should not be used to prevent coronary artery disease or other cardiovascular disease. The risks and benefits of HRT must be determined for a woman individually.
Mechanism of Action: The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use.
Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.
In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast carcinoma. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the treatment of breast carcinoma is rarely used today.
Pharmacokinetics:
Estradiol products are administered orally, intramuscularly, vaginally, and topically.
- Oral administration (estradiol): Estradiol is extensively metabolized in the GI mucosa during absorption and in the liver. Micronization of oral estradiol tablets slows oral absorption and decreases the first-pass effects in the liver and increases the normally poor bioavailability of estradiol. Absolute bioavailability of micronized estradiol is roughly 5 - 10% of an administered dose. Following oral administration, estradiol is rapidly transformed by the liver to estrone and estriol, the major circulating forms in the serum, by 17beta-hydroxysteroid dehydrogenase. The estrogens are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Estradiol, estrone, and estriol undergo glucuronide and sulfate conjugation to a variety of minor metabolites which are excreted primarily in the urine. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Some biliary excretion and entero-hepatic recycling of estradiol and its metabolites occurs. The plasma half-life of orally administered estradiol is approximately 1 - 2 hours at steady state; but other circulating estrogens persist longer.
- Transdermal administration (estradiol only): Transdermal administration of estradiol avoids first-pass metabolism and allows for continuous delivery of the hormone. Estradiol is minimally metabolized in the skin, thus higher therapeutic estradiol serum levels are present, and more closely approximate natural premenopausal concentrations. Minimal fluctuations in estradiol concentrations are seen with transdermal application. Transdermal estradiol has a short elimination half-life (~2 hours); serum estradiol concentrations return to postmenopausal levels within 4 - 8 hours of patch removal. Once in the serum, the distribution, metabolism and excretion of transdermally administered estradiol occurs through the same pathways as for oral administration.
- Vaginal administration (estradiol only): Estradiol is well absorbed through the vaginal mucous membranes. Drug delivery from intravaginal ring dosage forms is rapid as evidenced by Tmax values for estradiol of less than 1 hour. Following Cmax, serum estradiol concentrations decrease rapidly such that by 24 - 48 hours post-application of the dosage form, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. The vaginal dosage applied determines systemic hormone exposure; as a result, systemic as well as local tissue effects may occur. Different intravaginal ring devices are not interchangeable due to differences in dosage and efficacy in symptom control. For example, Estring® dosages are not effective for addressing vasomotor symptoms; low dose systemic delivery of estradiol from Estring® results in mean steady state serum estradiol estimates of 7 - 8.1 pg/ml; with an estradiol delivery rate of roughly 7.5 mcg/24 hours. Following administration of Femring™ 0.05 mg/day, the average serum estradiol concentration is 40.6 pg/ml; the corresponding apparent in vivo estradiol delivery rate is 0.052 mg/day. Following administration of Femring™ 0.10 mg/day, the average serum estradiol concentration is 76 pg/mL; the apparent in vivo delivery rate is 0.097 mg/day. Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations are slightly higher than estrone concentrations. Once absorbed systemically, the distribution, metabolism and excretion of estradiol delivered via vaginal application occurs via the same pathways as for oral administration.
- Intramuscular administration (estradiol cypionate and estradiol valerate only): These forms of estradiol are given as a depot injection in oil, which slows absorption after intramuscular injection. Esterification of estradiol to estradiol cypionate or valerate significantly increases the parenteral duration of action compared to aqueous estradiol formulations. Intramuscular administration of the cypionate esters of estradiol have more prolonged actions than the valerate esters, averaging 3 - 6 weeks and 2 - 3 weeks, respectively. However, IM dosage intervals are usually every 4 weeks for both cypionate and valerate esters of estradiol for most indications; dosage is adjusted to patient response.
- Topical administration (estradiol only): Topical administration of estradiol avoids first-pass metabolism and allows for continuous delivery of the hormone. Estradiol is minimally metabolized in the skin, thus higher therapeutic estradiol serum levels are present, and more closely approximate natural premenopausal concentrations. Estradiol topical emulsion (Estrasorb™) utilizes micellar nanoparticle technology for estradiol administration through the skin. Estradiol topical emulsion incorporates 17-? estradiol in a soy-based oil formulation, designed to deliver systemic levels of estrogen through the skin. Once in the serum, the distribution, metabolism and excretion of topically administered estradiol occurs through the same pathways as for oral administration.
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