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, which is secreted by the adrenal cortex, to estrone in the 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 gonadotropins seen in postmenopausal women.
Conjugated estrogens are water-soluble and are absorbed from the gastrointestinal tract after release from the drug formulation. The tablet releases conjugated estrogens slowly over several hours. Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of 1 × 0.625 mg and 1 × 1.25 mg tablets to healthy postmenopausal women.
Food effect: The pharmacokinetics of 0.45 mg and 1.25 mg estrogen tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3–13%. The changes to Cmax and AUC are not considered clinically meaningful, therefore estrogen tablets may be taken without regard to meals.
Table 2. Pharmacokinetic Parameters for Estrogen tablets:
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 0.625 mg | ||||
|---|---|---|---|---|
| PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
| Estrone | 87 (33) | 9.6 (33) | 50.7 (35) | 5557 (59) |
| Baseline-adjusted estrone | 64 (42) | 9.6 (33) | 20.2 (40) | 1723 (52) |
| Equilin | 31 (38) | 7.9 (32) | 12.9 (112) | 602 (54) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 0.625 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
| Total Estrone | 2.7 (43) | 6.9 (25) | 26.7 (33) | 75 (52) |
| Baseline-adjusted total estrone | 2.5 (45) | 6.9 (25) | 14.8 (35) | 46 (48) |
| Total Equilin | 1.8 (56) | 5.6 (45) | 11.4 (31) | 27 (56) |
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 1.25 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
| Estrone | 124 (30) | 10.0 (32) | 38.1 (37) | 6332 (44) |
| Baseline-adjusted estrone | 102 (35) | 10.0 (32) | 19.7 (48) | 3159 (53) |
| Equilin | 59 (43) | 8.8 (36) | 10.9 (47) | 1182 (42) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 1.25 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
| Total Estrone | 4.5 (39) | 8.2 (58) | 26.5 (40) | 109 (46) |
| Baseline-adjusted total estrone | 4.3 (41) | 8.2 (58) | 17.5 (41) | 87 (44) |
| Total equilin | 2.9 (42) | 6.8 (49) | 12.5 (34) | 48 (51) |
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 concentration 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 a 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 portion 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.
No pharmacokinetic studies were conducted with estrogens in specific populations, including patients with renal or hepatic impairment.
Conjugated estrogens are water-soluble and are well-absorbed through the skin, mucous membranes, and gastrointestinal tract after release from the drug formulation.
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 concentration 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 a 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.
No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
Data from a single-dose drug-drug interaction study involving oral CE and MPA indicate that the pharmacokinetic dispositions of both drugs are not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with conjugated estrogens.
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 (Hypericum perforatum) preparations, 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.
Conjugated estrogens are water soluble and are well-absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.
A bioavailability study was conducted in 24 postmenopausal women with atrophic vaginitis. The mean (SD) pharmacokinetic parameters for unconjugated estrone, unconjugated estradiol, total estrone, total estradiol and total equilin following 7 once-daily doses of estrogens vaginal cream 0.5 g is shown in Table 2.
Table 2. Mean ± SD Pharmacokinetic Parameters of Estrogens Following Daily Administration (7 Days) of Estrogens Vaginal Cream 0.5 g in 24 Postmenopausal Women:
| Pharmacokinetic Profiles of Unconjugated Estrogens Vaginal Cream 0.5 g | |||
|---|---|---|---|
| PK Parameters Arithmetic Mean ± SD | Cmax (pg/mL) | Tmax (hr) | AUCss (pg•hr/mL) |
| Estrone | 42.0 ± 13.9 | 7.4 ± 6.2 | 826 ± 295 |
| Baseline-adjusted estrone | 21.9 ± 13.1 | 7.4 ± 6.2 | 365 ± 255 |
| Estradiol | 12.8 ± 16.6 | 8.5 ± 6.2 | 231 ± 285 |
| Baseline-adjusted estradiol | 9.14 ± 14.7 | 8.5 ± 6.2 | 161 ± 252 |
| Pharmacokinetic Profiles of Conjugated Estrogens Vaginal Cream 0.5 g | |||
| PK Parameters Arithmetic Mean ± SD | Cmax (ng/mL) | Tmax (hr) | AUCss (ng•hr/mL) |
| Total estrone | 0.60 ± 0.32 | 6.0 ± 4.0 | 9.75 ± 4.99 |
| Baseline-adjusted total estrone | 0.40 ± 0.28 | 6.0 ± 4.0 | 5.79 ± 3.7 |
| Total estradiol | 0.04 ± 0.04 | 7.7 ± 5.9 | 0.70 ± 0.42 |
| Baseline-adjusted total estradiol | 0.04 ± 0.04 | 7.7 ± 6.0 | 0.49 ± 0.38 |
| Total equilin | 0.12 ± 0.15 | 6.1 ± 4.7 | 3.09 ± 1.37 |
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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to 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 a 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 portion 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.
No pharmacokinetic studies were conducted in specific populations, including patients with renal or hepatic impairment.
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