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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 its 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.



In a multiple-dose study, 125 patients were treated for 28 days once daily with placebo or 1.15 grams, 2.30 grams, or 3.45 grams of Estrasorb containing 2.5 mg of estradiol per gram. The mean change from baseline in serum estradiol concentrations increased in a dose-dependent manner compared with placebo (Figure 1 below).

Figure 1: Mean serum estradiol concentrations (pg/mL) following topical application of placebo or 1.15 Grams, 2.30 Grams or 3.45 Grams of Estrasorb containing 2.5 mg of estradiol per Gram

Mean serum estradiol concentrations - Illustration

Serum estradiol concentrations were also assessed in a second study involving 200 postmenopausal women, who applied either a 3.45 gram daily dose of Estrasorb (containing 2.5 mg of estradiol per gram; n = 100) or placebo (n = 100) for 12 weeks. Trough estradiol concentrations in the Estrasorb treatment group increased from a mean of 8.9 pg/mL at baseline to 58.6 pg/mL and 70.2 pg/mL at Weeks 2 and 4, respectively (Figure 2). Trough levels of Estrasorb remained at a plateau throughout the rest of the study: 67.3 pg/mL at Week 8 and 63.0 pg/mL at the end of the study.

Figure 2: Mean (SE) Trough Serum Estradiol Concentrations Following Daily Topical Application of 3.45 Grams of Estrasorb Containing 2.5 mg of Estradiol per Gram for 12 weeks.

Mean (SE) Trough Serum Estradiol Concentrations - Illustration

SE = Standard error of the mean.

Application of sunscreen 10 minutes prior to the application of Estrasorb increased the exposure to estradiol by approximately 35%. When sunscreen is applied 25 minutes after the application of Estrasorb, the increase in exposure to estradiol was approximately 15%. (See PRECAUTIONS.)


No specific investigation of the tissue distribution of estradiol absorbed from Estrasorb in humans has been conducted. 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 intestines, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists 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.

Special Populations

Estrasorb was only investigated in postmenopausal women. Estrasorb has not been studied in patients with hepatic or renal impairment.

Drug Interactions

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 may result in side effects.

Clinical Studies

Effects on Vasomotor Symptoms

In a 12-week randomized, placebo-controlled clinical trial, a total of 200 postmenopausal women (average age 52 ± 6 years, 79% Caucasian in the Estrasorb treatment group; average age 51.8 ± 6 years, 72% Caucasian in the placebo treatment group) were assigned to receive Estrasorb (3.45 grams containing 2.5 mg of estradiol per gram) or placebo for a 12 weeks duration. Estrasorb was shown to be statistically better than placebo at Weeks 4 and 12 for relief of both the frequency and severity of moderate to severe vasomotor symptoms (p-value < 0.001 for Weeks 4 and 12). Frequency results are shown in Table 1. Severity results are shown in Table 2.

Table 1: Mean Number and Mean Change From Baseline in the Number of Moderate to Severe Vasomotor Symptoms Per Day (Intent-To-Treat Population)

Time point Treatment Group
Placebo Estrasorb
Baseline (observed value) (N = 100) (N = 100)
  Mean Number of Hot Flushes (SD) 13.63 (5.48) 13.05 (5.78)
Week 4 (N = 97) (N = 96)
  Mean Number of Hot Flushes (SD) 7.46 (6.42) 4.42 (5.60)
  Mean Change from Baseline (SD) – 5.97 (4.76) – 8.56 (6.19)
  P-value vs. Placebo NA <0.001
Week 12 (N = 90) (N = 90)
  Mean Number of Hot Flushes (SD) 5.88 (6.17) 2.00 (3.64)
  Mean Change from Baseline (SD) – 7.20 (5.39) – 11.11 (6.84)
  P-value vs. Placebo NA <0.001
SD = Standard Deviation; NA = Not applicable

Table 2: Mean Change from Baseline in the Severity Scorea of Hot Flushes Per Day, Intent-to-Treat Population, Most Recent Value Carried Forward

Time point Treatment Group
Placebo Estrasorb
Baseline (observed value) (N = 100) (N = 100)
Mean Severity Score per Day (SD) 2.44 (0.37) 2.36 (0.36)
Week 4 (N = 97) (N = 96)
  Mean Severity Score per Day (SD) 1.99 (0.81) 1.47 (1.03)
  Mean Change from Baseline (SD) - 0.45 (0.75) - 0.89 (1.04)
  P-value versus Placebo NA < 0.001
Week 12 (N = 90) (N = 90)
  Mean Severity Score per Day (SD) 1.88 (0.98) 0.92 (1.00)
  Mean Change from Baseline (SD) -0.55 (0.91) -1.44 (1.04)
  P-value versus Placebo NA < 0.001
SD = Standard deviation; NA = Not applicable
a The severity score per day is determined by calculating the sum of recorded daily severity and dividing this number by the total number of hot flushes on that day.

Potential for estradiol transfer

Estradiol was detected on the skin at 2 and 8 hours post-application. Washing the application area with soap and water 8 hours post-application removed detectable estradiol from the application site.

Upon physical contact of Estrasorb application sites by adult males at 2 and 8 hours post-application over a two-day period in a second study, a mean increase of approximately 25% in serum estradiol concentration was identified. (See DOSAGE AND ADMINISTRATION.)

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) 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 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 3 below.


Eventc Relative Risk Prempro vs Placebo at 5.2 Years (95% CI*) Placebo
n = 8102
n = 8506
Absolute Risk per 10,000 Person-years
CHD events 1.29 (1.02-1.63) 30 37
Non-fatal MI 1.32 (1.02-1.72) 23 30
CHD death 1.18 (0.70-1.97) 6 7
Invasive breast cancerb 1.26 (1.00-1.59) 30 38
Stroke 1.41 (1.07-1.85) 21 29
Pulmonary embolism 2.13 (1.39-3.25) 8 16
Colorectal cancer 0.63 (0.43-0.92) 16 10
Endometrial cancer 0.83 (0.47-1.47) 6 5
Hip fracture 0.66 (0.45-0.98) 15 10
Global Index c 1.15 (1.03-1.28) 151 170
Deep vein thrombosisd 2.07 (1.49-2.87) 13 26
Vertebral fracturesd 0.66 (0.44-0.98) 15 9
Other osteoporotic fracturesd 0.77 (0.69-0.86) 170 131
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,” absolute excess risks per 10,000 person-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 person-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 person-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 Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy 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 and WARNINGS, Dementia.)

Last reviewed on RxList: 7/22/2011
This monograph has been modified to include the generic and brand name in many instances.


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