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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.
Estradiol diffuses across intact skin and into the systemic circulation by a passive absorption process, with diffusion across the stratum corneum being the rate-limiting factor.
In a 14-day, Phase 1, multiple-dose study, Divigel® demonstrated linear and approximately dose-proportional estradiol pharmacokinetics at steady state for both AUC0-24 and Cmax following once daily dosing to the skin of either the right or left upper thigh (Table 1).
Table 1: Mean (%CV) Pharmacokinetic Parameters for
Estradiol (uncorrected for baseline) on Day 14 Following Multiple Daily Doses of
|Parameter (units)||Divigel® 0.25 g||Divigel® 0.5 g||Divigel® 1.0 g|
|AUC0-24 (pg•h/mL)||236 (94)||504 (149)||732 (81)|
|Cmax (pg/mL)||14.7 (84)||28.4 (139)||51.5 (86)|
|Cavg (pg/mL)||9.8 (92)||21 (148)||30.5 (81)|
|tmax* (h)||16 (0, 72)||10 (0, 72)||8 (0, 48)|
|*Median (Min, Max).|
Steady-state serum concentration of estradiol are achieved by day 12 following daily application of Divigel® to the skin of the upper thigh. The mean (SD) serum estradiol levels following once daily dosing at day 14 are shown in Figure 1.
Figure 1: Mean (SD) Serum Estradiol Concentrations
(Values Uncorrected for Baseline) on Day 14 Following Multiple Daily Doses of
The effect of sunscreens and other topical lotions on the systemic exposure of Divigel® has not been evaluated. Studies conducted using topical estrogen gel approved products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels.
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.
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 from Divigel® avoids first pass metabolism and provides estradiol/estrone ratios at steady state in the range of 0.42 to 0.65.
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The apparent terminal half-life for estradiol was about 10 hours following administration of Divigel®.
Divigel® has been studied only in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
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, itraconazole, ritonavir, and grapefruit juice, may increase plasma concentrations of estrogens and result in side effects.
Potential for Estradiol Transfer and Effects of Washing
As with most topical products, there is a potential for estradiol transfer following physical contact with Divigel® application sites. The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 g of Divigel® (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh- to- arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive.
The effect of application site washing on skin surface levels and serum concentrations of estradiol was determined in 16 healthy postmenopausal women after application of 1.0 g of Divigel® to a 200 cm² area on the thigh. Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30-38% decrease in the mean total 24-hour exposure to estradiol.
Effects on Vasomotor Symptoms
A randomized, double-blind, placebo-controlled trial evaluated the efficacy of 12-week treatment with three different daily doses of Divigel® for vasomotor symptoms in 495 postmenopausal women (86.5% White; 10.1% Black) between 34 and 89 years of age (mean age 54.6) who had at least 50 moderate to severe hot flushes per week at baseline (2 week period prior to treatment). Subjects applied placebo, Divigel® 0.25 g (0.25 mg estradiol), Divigel® 0.5 g (0.5 mg estradiol) or Divigel® 1.0 g (1.0 mg estradiol) once daily to the thigh. Reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes were statistically significant for the 0.5 g/day and the 1.0 g/day Divigel® doses when compared to placebo at week 4. Statistically significant reductions in both the median daily frequency and the median daily severity of moderate to severe hot flushes for the Divigel® 0.25 g/day dose when compared to placebo were delayed to week 7. There were statistically significant reductions in median daily frequency and severity of hot flushes for all three Divigel® doses (0.25 g/day, 0.5 g/day and 1.0 g/day) compared to placebo at week 12. See Table 2 for results.
Table 2: Summary of Change From Baseline in the Median
Daily Frequency and Severity of Hot Flushes during Divigel® Treatment (ITT
|Frequency of Daily Hot Flushes|
|Median Change: Week 4||-5.00||-5.73||-7.20||-3.63|
|Median Change: Week 7||-6.62||-7.14||-7.71||-4.37|
|Median Change: Week 12||-6.88||-7.29||-8.35||-4.48|
|Severity of Daily Hot Flushes|
|Median Change: Week 4||-0.07||-0.18||-0.47||-0.04|
|Median Change: Week 7||-0.24||-0.46||-1.06||-0.06|
|Median Change: Week 12||-0.33||-0.56||-1.69||-0.13|
|†p-values from the van Elteren's test stratified by pooled center; comparison in median change was significant if p<0.05|
Women's Health Initiative Studies
The Women's Health Initiative (WHI) enrolled a total of 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 (CE 0.625 mg/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 estrogen-plus-progestin 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 of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 3.
Table 3: Relative And Absolute Risk Seen In The
Estrogen-Alone Substudy Of WHIa
|Event||Relative Risk CE vs. Placebo (95% nCIa)||Placebo
n = 5,429
n = 5,310
|Absolute Risk per 10,000 Women-Years|
|CHD eventsb||0.95 (0.79- 1.16)||56||53|
|Nonfatal MIb||0.91 (0.73-1.14)||43||40|
|CHD deathb||1.01 (0.71- 1.43)||16||16|
|Deep vein thrombosisb,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 (0.88-1.32)||78||81|
|Global indexc,f||1.01 (0.91-1.12)||190||192|
|a Nominal 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 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.)
Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer incidence from the estrogen-alone substudy, after an average followup of 7.1 years, reported no overall difference for 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 3).
The estrogen-plus-progestin substudy was also stopped early because, 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 age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), are presented in Table 4 below. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.
Table 4: Relative And Absolute Risk Seen in the
Estrogen-Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa
|Eventc||Relative Risk CE/MPA vs. Placebo (95% nCIb)||Placebo
n = 8102
n = 8506
|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|
|Ischemic stroke||1.44 (1.09 -1.90)||18||26|
|Deep vein thrombosis||1.95 (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)||16||9|
|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||11|
|Vertebral fractures||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-cause mortality (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 of the WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were aged 65 to 69 years, 36% were 70 to 74 years, and 19% 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 estrogenalone group was 1.49 (95% 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% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg) daily 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 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, 1.21-3.48) 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% CI 1.19-2.60). It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING, WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
Last reviewed on RxList: 6/6/2012
This monograph has been modified to include the generic and brand name in many instances.
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