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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 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 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, 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. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.
In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal ring) rapidly increased serum estradiol (E2) levels.The time to attain peak serum estradiol levels (Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean (range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged (see Table 1).
The initial estradiol peak post-application of the second ring in the same women resulted in ~38% lower Cmax, apparently due to reduced systemic absorption via the treated vaginal epithelium. The relative systemic exposure from the initial peak of ESTRING accounted for approximately 4% of the total estradiol exposure over the 12 week period.
The release of estradiol from ESTRING (estradiol vaginal ring) was demonstrated in a Phase II study of 222 post- menopausal women who inserted up to four rings consecutively at three month intervals. Systemic delivery of estradiol from ESTRING resulted in mean steady state serum estradiol estimates of 7.8, 7.0, 7.0, 8.1 pg/mL at weeks 12, 24, 36, and 48, respectively. Similar reproducibility is also seen in levels of estrone. The systemic exposure to estradiol and estrone was within the range observed in untreated women after the first eight hours.
In postmenopausal women, mean dose of estradiol systemically absorbed unchanged from ESTRING (estradiol vaginal ring) is ~8% [95% CI: 2.8-12.8%] of the daily amount released locally.
TABLE 1: PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE
ESTRING (estradiol vaginal ring) APPLICATION
| Css-48 hr
| a n=14
bBased on means
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex-hormone binding globulin (SHBG) and albumin.
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application of ESTRING (estradiol vaginal ring) in a Phase I study was 5% and 8%, respectively, of the daily released amount.
ESTRING (estradiol vaginal ring) has not been studied in patients with hepatic or renal impairment.
No formal drug interactions studies have been done with ESTRING (estradiol vaginal ring) .
In vitro and in vivo studies have shown that systemic estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in systemic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
Effects on vulvar and vaginal atrophy.
Two pivotal controlled studies have demonstrated the efficacy of ESTRING (estradiol vaginal ring) in the treatment of postmenopausal urogenital symptoms due to estrogen deficiency.
In a U.S. study where ESTRING (estradiol vaginal ring) was compared with conjugated estrogens vaginal cream, no difference in efficacy between the treatment groups was found with respect to improvement in the physician's global assessment of vaginal symptoms (83% and 82% of patients receiving ESTRING (estradiol vaginal ring) and cream, respectively) and in the patient's global assessment of vaginal symptoms (83% and 82% of patients receiving ESTRING (estradiol vaginal ring) and cream, respectively) after 12 weeks of treatment. In an Australian study, ESTRING (estradiol vaginal ring) was also compared with conjugated estrogens vaginal cream and no difference in the physician's assessment of improvement of vaginal mucosal atrophy (79% and 75% for ESTRING (estradiol vaginal ring) and cream, respectively) or in the patient's assessment of improvement in vaginal dryness (82% and 76% for ESTRING (estradiol vaginal ring) and cream, respectively) after 12 weeks of treatment.
In the U.S. study, symptoms of dysuria and urinary urgency improved in 74% and 65%, respectively, of patients receiving ESTRING (estradiol vaginal ring) as assessed by the patient. In the Australian study, symptoms of dysuria and urinary urgency improved in 90% and 71%, respectively, of patients receiving ESTRING (estradiol vaginal ring) as assessed by the patient.
In both studies, ESTRING (estradiol vaginal ring) and conjugated estrogens vaginal cream had a similar ability to reduce vaginal pH levels and to mature the vaginal mucosa (as measured cytologically using the maturation index and/or the maturation value) after 12 weeks of treatment. In supportive studies, ESTRING (estradiol vaginal ring) was also shown to have a similar significant treatment effect on the maturation of the urethral mucosa.
Endometrial overstimulation, as evaluated in non-hysterectomized patients participating in the U.S. study by the progestogen challenge test and pelvic sonogram, was reported for none of the 58 (0%) patients receiving ESTRING (estradiol vaginal ring) and 4 of the 35 patients (11%) receiving conjugated estrogens vaginal cream.
Of the U.S. women who completed 12 weeks of treatment, 95% rated product comfort for ESTRING (estradiol vaginal ring) as excellent or very good compared with 65% of patients receiving conjugated estrogens vaginal cream, 95% of ESTRING (estradiol vaginal ring) patients judged the product to be very easy or easy to use compared with 88% of cream patients, and 82% gave ESTRING (estradiol vaginal ring) an overall rating of excellent or very good compared with 58% for the cream.
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or in combination with medroxyprogesterone acetate (MPA 2.5 mg) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE/MPA substudy), colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
The estrogen-alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the estrogen-alone substudy, which included 10,739 women (average age 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 6.8 years are presented in Table2.
TABLE 2: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN
ALONE SUBSTUDY OF WHI a
|Eventc|| Relative Riska
CE vs. Placebo
n = 5,429
n = 5,310
|Absolute Risk per 10,000 Women-Years|
|CHD eventsb||0.95 (0.79-1.16)||56||53|
|Non-fatal MIb||0.91 (0.73-1.14)||43||40|
|CHD deathb||1.01 (0. 71-1.43)||16||16|
|Deep vein trombosisb,d||1.47 (1.06-2.06)||15||23|
|Pulmonary embolismb||1.37 (0.90-2.07)||10||14|
|Invasive breast cancerb||0.80 (0.62-1.04)||34||28|
|Colorectal cancerc||1.08 (0.75-1.55)||16||17|
|Hip fracturec||0.61 (0.41-0.91)||17||11|
|Vertebral fracturesc,d||0.62 (0.42-0.93)||17||11|
|Total fracturesc,d||0.70 (0.63-0.79)||195||139|
|Death due to other causesc,e||1.08 (0.88-1.32)||50||53|
|Overall mortalityc,d||1.04 (0.88-1.22)||78||81|
|Global index b,f||1.01 (0.91-1.12)||190||192|
| aNominal confidence intervals unadjusted for
multiple looks and multiple comparisons.
b Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
c Results are based on an average follow-up of 6.8 years.
d Not included in Global index.
e All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.
f A subset of the events was combined in a "global index" defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a non significant 2 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference from primary CHD events (nonfatal MI, Silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 2).
The estrogen-plus-progestin substudy was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28).
For those outcomes included in the WHI "global index" that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 6 more CHD events, 7 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 7 fewer colorectal cancers and 5 fewer hip fractures. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Results of the estrogen-plus-progestin substudy which included 16,608 women (average of 63 years, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent. Other, are presented in Table 3 below. These results reflect centrally adjudicated data, after an average follow-up of 5.6 years .
TABLE 3: RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN-
PLUS-PROGESTIN SUBSTUDY OF WHI AT AN AVERAGE OF 5.6 YEARa
|Event c|| Relative Risk CE/MPA vs. placebo
n = 8,102
n = 8,506
|Absolute Risk per 10,000 Women-Years|
|CHD events||1.24 (1.00-1.54)||33||39|
|Non-fatal MI||1.28 (1.00-1. 63)||25||31|
|CHD death||1.10 (0.70-1.75)||8||8|
|All strokes||1.31 (1.02-1.68)||24||31|
|Ischenic Stroke||1.44 (1.09-1.90)||18||26|
|Deep vein thrombosis||2.13 (1.43-2.67)||13||26|
|Pulmonary embolism||2.13 (1.45-3.11)||8||18|
|Invasive breast cancerc||1.24 (1.01-1.54)||33||41|
|Invasive Colorectal cancer||0.56 (0.38-0.81)||10||16|
|Endometrial cancer||0.81 (0.48-1.36)||7||6|
|Cervical cancer||1.44 (0.47-4.42)||1||2|
|Hip fracture||0.67 (0.47-0.96)||16||9|
|Vertebral fracture||0.65 (0.46-0.92)||17||11|
|Lower arm/wrist fractures||0.71 (0.59-0.85)||62||44|
|Total fractures||0.76 (0.69-0.83)||199||152|
| a Results are based on centrally adjudicated data.
Mortality data was not part of the adjudicated data;however, data at 5.2
years of follow-up showed no difference between the groups in terms of all-causemortality
(RR 0.98, 95% nCI 0.82-1.18).
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.
Women's Health Initiative Memory Study
The estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45 percent were aged 65 to 69 years, 36 percent were 70 to 74 years, and 19 percent were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the incidence of probable dementia(primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group (25 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen-alone group was 1.49 (95 percent confidence interval (CI), 0.83-2.66) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
The estrogen plus progestin WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were aged 65 to 69 years, 35 percent were 70 to 74 years, and 18 percent were 75 years of age and older) to evaluate the effects of CE/MPA ( 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen-plus-progestin (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95 percent CI, 1.21-3.48) compared to placebo.
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
Last reviewed on RxList: 10/16/2008
This monograph has been modified to include the generic and brand name in many instances.
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