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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 mcg 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.
The decline of ovarian estrogen production that accompanies menopause or oophorectomy results in the acceleration of bone loss and bone resorption. Bone resorption is increased more than bone formation especially in the early years of menopause where bone loss is the greatest. In some women, these changes will eventually lead to decreased bone mass, osteoporosis and increased risk for fractures, particularly that of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women.
Postmenopausal women with low serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin (SHBG) have an increased risk of hip and vertebral fractures. Postmenopausal estrogen therapy decreases bone resorption, helping to reestablish balance between resorption and formation. This effect appears to be effective for as long as treatment is continued.
The bioavailability of estradiol following application of a Menostar (estradiol transdermal system) transdermal system, relative to that of a transdermal system delivering 25 mcg/day, was investigated in 18 healthy postmenopausal women mean age 66 years (range 60-80 years). The mean serum estradiol concentrations upon administration of the two patches to the lower abdomen are shown in Figure 1. Transdermal administration of Menostar produced geometric mean serum concentration (Cavg) of estradiol of 13.7 pg/mL. No patches failed to adhere during the one week application period of both transdermal systems. Following application of the Menostar (estradiol transdermal system) transdermal system to the abdomen, it is estimated to provide an average nominal in-vivo daily delivery of 14 mcg estradiol/day.
The Menostar transdermal delivery system continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route.
Figure 1 : Mean Uncorrected Serum 17β-Estradiol Concentrations
vs. Time Profile Following Application of Menostar (estradiol transdermal system) and Climara® 6.5 cm²
Table 1 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of Menostar (estradiol transdermal system) using baseline uncorrected serum concentrations.
Table 1 : Summary of Estradiol Pharmacokinetic Parameters
|Climara® 6.5 cm²||25||4151||37.2||24.7||42||20.4|
Pharmacokinetic parameters are expressed in geometeric means except for the tmax which represents the median estimate and the Cmin which is expressed as the arithmetic mean.
The estimated estradiol daily delivery rate for Climara 6.5 cm² is quoted from the Climara labeling.
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. In the clinical study with 208 patients on Menostar (estradiol transdermal system) , SHBG concentration (mean ± SD) remained essentially unchanged over the 2 year period (baseline 45.1 ± 20.1 nmol/L, 24 month visit 46.4 ± 20.9 nmol/L).
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.
Geriatric: The efficacy and safety of Menostar (estradiol transdermal system) has been studied in women between 60 and 80 years of age, with approximately half over 65 years old.
Pediatric: No pharmacokinetic study for Menostar (estradiol transdermal system) has been conducted in a pediatric population.
Gender: Menostar (estradiol transdermal system) is indicated for use in postmenopausal women only.
Race: No studies were done to determine the effect of race on the pharmacoki-netics of Menostar.
Patients with Renal Impairment: Total estradiol serum levels are higher in postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.
Patients with Hepatic Impairment: Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.
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. 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 therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itra-conazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.
In a Menostar (estradiol transdermal system) pharmacokinetic study with 18 postmenopausal women, no patches failed to adhere during the one week application period.
The efficacy of Menostar (estradiol transdermal system) in the prevention of postmenopausal osteoporosis was investigated in a 2-year double blind, placebo-controlled, multicenter study in the United States. A total of 417 postmenopausal women, 60 to 80 years old, with an intact uterus were enrolled in the study. All patients received supplemental calcium and vitamin D.
Menostar (estradiol transdermal system) produced larger increases in bone mass than placebo as reflected by dual-energy x-ray absorptiometric (DEXA) measurements of hip and lumbar spine BMD. The changes in BMD from baseline were statistically significantly (p < 0.001) greater during treatment with Menostar (estradiol transdermal system) than during treatment with placebo for hip and spine after 1 and 2 years.
At lumbar spine Menostar (estradiol transdermal system) increased BMD by 2.3% after 1 year and 3% after 2 years compared with a 0.5% increase after 1 and 2 years of treatment with placebo. At the hip Menostar (estradiol transdermal system) increased BMD by 0.9% after one year and 0.84% after two years compared with a mean decrease of 0.22% after 1 year and 0.71% after 2 years of placebo treatment (see Table 2 below).
Table 2 : Mean Percent BMD Change from Baseline in Lumbar
Spine and Total Hip (Full Analysis Set)
|Lumbar spine||Total hip|
N = 208
N = 209
N = 208
N = 209
|n = 189||n = 186||n = 189||n = 184|
|12-month Endpoint||+2.29||+0.51||< 0.001||12-month Endpoint||+0.9||-0.22||< 0.001|
|n = 189||n = 186||n = 189||n = 185|
|24-month Endpoint||+2.99||+0.54||< 0.001||24-month Endpoint||+0.84||-0.71||< 0.001|
|N = total number of patients; n = number of patients with data available for each variable|
The BMD data of the study were analyzed according to baseline estradiol levels of the patients. Overall, estimated treatment effects on lumbar spine and total hip BMD after 2 years were approximately twice as large in the subgroup with baseline estradiol levels < 5 pg/mL than in the subgroup with baseline estradi-ol levels ≥ 5 pg/mL [Table 3].
Table 3 : Mean percent change in lumbar spine and total hip BMD at 24 months by subgroups of baseline estradiol level ( < 5 pg/mL, ≥
|Lumbar spine||Total hip|
|Baseline estradiol levels||Menostar||Placebo||Treatment difference||Menostar||Placebo||Treatment difference|
|< 5 pg/mL||n = 101||n = 97||n = 101||n = 96|
(p < 0.001)
(p < 0.001)
|≥ 5 pg/mL||n = 88||n = 89||n = 88||n = 89|
(p = 0.002)
(p = 0.045)
|n = number of patients with data available for each variable|
Menostar (estradiol transdermal system) therapy also resulted in consistent, statistically significant suppression of bone turnover, as reflected by changes in serum and urine markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and bone resorption (carboxyterminal telopeptide of type 1 collagen (ICTP) and the urinary deoxypryridoline/creatinine ratio).
Women's Health Initiative Studies
The WHI-enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg) alone per day or the use of oral conjugated estrogens (CE 0.625 mg) plus 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 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, 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. Results of the estrogen-alone substudy, which included 10,739 women (average age 63 years, range 50 to 79: 75.3 percent white, 15 percent black, 6.1 percent Hispanic), after an average follow-up of 6.8 years are presented in Table 4.
Table 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE ESTROGEN
ALONE SUBSTUDY OF WHIa
CE vs Placebo
at 6.8 Years
n = 5310
n = 5429
|Absolute Risk per 10,000 Women-years|
|CHD events||0.91 (0.75-1.12)||49||54|
|Non-fatal MI||0.89 (0.7-1.12)||37||41|
|CHD death||0.94 (0.65-1.36)||15||16|
|Invasive breast cancer||0.77 (0.59-1.01)||26||33|
|Pulmonary embolism||1.34 (0.87-2.06)||13||10|
|Colorectal cancer||1.08 (0.75-1.55)||17||16|
|Hip fracture||0.61 (0.41-0.91)||11||17|
|Death due to causes other than the events above||1.08 (0.88-1.32)||53||50|
|Global Indexb||1.01 (0.91-1.12)||192||190|
|Deep vein thrombosisc||1.47 (1.04-2.08)||21||15|
|Vertebral fracturesc||0.62 (0.42-0.93)||11||17|
|Total fracturesc||0.7 (0.63-0.79)||139||195|
|a adapted from JAMA, 2004; 291:1701-1712
b 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
c Not included in Global Index
*Nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risks 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 nonsignificant 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.)
The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:
Table 5 : RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY
CE/MPA vs placebo
at 5.2 Years
n = 8506
n = 8102
|Absolute Risk per
|CHD events||1.29 (1.02-1.63)||37||30|
|Non-fatal MI||1.32 (1.02-1.72)||30||23|
|CHD death||1.18 (0.7-1.97)||7||6|
|Invasive breast cancerb||1.26 (1-1.59)||38||30|
|Pulmonary embolism||2.13 (1.39-3.25)||16||8|
|Colorectal cancer||0.63 (0.43-0.92)||10||16|
|Endometrial cancer||0.83 (0.47-1.47)||5||6|
|Hip fracture||0.66 (0.45-0.98)||10||15|
|Death due to causes other than the events above||0.92 (0.74-1.14)||37||40|
|Global Indexc||1.15 (1.03-1.28)||170||151|
|Deep vein thrombosisd||2.07 (1.49-2.87)||26||13|
|Vertebral fracturesd||0.66 (0.44-0.98)||9||15|
|Other osteoporotic fracturesd||0.77 (0.69-0.86)||131||170|
|a adapted from JAMA, 2002; 288:321-333
b includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
c 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, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
d not included in Global Index
*nominal confidence intervals unadjusted for multiple looks and multiple comparisons
For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)
Women's Health Initiative Memory Study
The estrogen-alone WHIMS, a substudy of the WHI study, 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 postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
The estrogen plus progestin WHIMS substudy of WHI enrolled 4,532 predominantly postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% 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/progestin group (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% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
Last reviewed on RxList: 3/27/2009
This monograph has been modified to include the generic and brand name in many instances.
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