Premarin Mechanism of Action

Pharmacology: Pharmacodynamics: Currently, there are no pharmacodynamic data known for CE alone.
Mechanism of Action: 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 post-menopausal 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 post-menopausal women.
Effects on vasomotor symptoms: In the first year of the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, a total of 2,805 post-menopausal women (average age 53.3 ± 4.9 years) were randomly assigned to one of eight treatment groups, receiving either placebo or conjugated estrogens, with or without medroxyprogesterone acetate. Efficacy for vasomotor symptoms was assessed during the first 12 weeks of treatment in a subset of symptomatic women (n = 241) who had at least seven moderate-to-severe hot flushes daily, or at least 50 moderate-to-severe hot flushes during the week before randomization. With CE (0.3 mg, 0.45 mg, and 0.625 mg tablets), the decrease of both the frequency and severity of moderate-to-severe vasomotor symptoms was shown to be statistically improved compared with placebo at weeks 4 and 12. Table 1 shows the observed mean number of hot flushes in the CE 0.3 mg, 0.45 mg, and 0.625 mg and placebo treatment groups over the initial 12-week period. (See Table 1.)

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Effects on vulvar and vaginal atrophy: Results of vaginal maturation indexes at cycles 6 and 13 showed that the differences from placebo were statistically significant (p < 0.001) for all treatment groups.
Effect on bone mineral density: Health and Osteoporosis, Progestin and Estrogen (HOPE): Study The HOPE study was a double-blind, randomized, placebo/active-drug-controlled, multicenter study of healthy post-menopausal women with an intact uterus. Subjects (mean age 53.3 ± 4.9 years) were 2.3 ± 0.9 years on average since menopause and took one 600 mg tablet of elemental calcium (Caltrate) daily. Subjects were not given Vitamin D supplements. They were treated with CE 0.625 mg, 0.45 mg, 0.3 mg, or placebo. Prevention of bone loss was assessed by measurement of bone mineral density (BMD), primarily at the anteroposterior lumbar spine (L2 to L4). Secondarily, BMD measurements of the total body, femoral neck, and trochanter were also analyzed. Serum osteocalcin, urinary calcium, and N telopeptide were used as bone turnover markers (BTM) at cycles 6, 13, 19, and 26.
Intent-to-treat subjects: All active treatment groups showed significant differences from placebo in each of the four BMD endpoints at cycles 6, 13, 19, and 26. The percent changes from baseline to final evaluation are shown in Table 2. (See Table 2.)

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The bone turnover markers serum osteocalcin and urinary N-telopeptide significantly decreased (p < 0.001) in all active-treatment groups at cycles 6, 13, 19, and 26 compared with the placebo group. Larger mean decreases from baseline were seen with the active groups than with the placebo group. Significant differences from placebo were seen less frequently in urine calcium.
Effects on female hypogonadism: CE Tablets: In clinical studies of delayed puberty due to female hypogonadism, breast development was induced by doses as low as 0.15 mg. The dosage may be gradually titrated upward at 6 to 12-month intervals as needed to achieve appropriate bone age advancement and eventual epiphyseal closure. Available data suggest that chronic dosing with 0.625 mg is sufficient to induce artificial cyclic menses with sequential progestin treatment and to maintain bone mineral density after skeletal maturity is achieved.
Women's Health Initiative Studies (WHI): The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy post-menopausal women in two substudies to assess the risks and benefits of conjugated estrogens (CE) [0.625 mg daily] alone or in combination with MPA [0.625 mg/2.5 mg daily] compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) defined as non-fatal myocardial infarction (MI), silent MI and CHD death, with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE alone or CE plus MPA on menopausal symptoms.
WHI Estrogen-alone Substudy: The WHI 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 63.6 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 7.1 years, are presented in the table below.
In the estrogen-alone substudy of WHI, there was no significant overall effect on the relative risk (RR) of CHD (RR 0.95, 95% nominal confidence interval [nCI] 0.78-1.16); a slightly elevated RR of CHD was reported in the early follow-up period and diminished over time. There was no significant effect on the RR of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04) or colorectal cancer (RR 1.08, 95% nCI 0.75-1.55) reported. Estrogen use was associated with a statistically significant increased risk of stroke (RR 1.33, 95% nCI 1.05-1.68) and deep vein thrombosis (DVT) (RR 1.47, 95% nCI 1.06-2.06). The RR of PE (RR 1.37, 95% nCI 0.90-2.07) was not significantly increased. A statistically significant reduced risk of hip, vertebral and total fractures was reported with estrogen use (RR 0.65, 95% nCI 0.45-0.94), (RR 0.64, 95% nCI 0.44-0.93), and (RR 0.71, 95% nCI 0.64-0.80), respectively. The estrogen-alone substudy did not report a statistically significant effect on death due to other causes (RR 1.08, 95% nCI 0.88-1.32) or an effect on overall mortality risk (RR 1.04, 95% nCI 0.88-1.22). These confidence intervals are unadjusted for multiple looks and multiple comparisons. (See Table 3.)

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Primary results of the Estrogen-alone substudy stratified by age at baseline is described in the following table. (See Table 4.)

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Timing of initiation of estrogen therapy from the start of menopause may affect the overall risk-benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50-59 years of age, a non-significant trend towards reduced risk for CHD and overall mortality compared with placebo in women who initiated hormone therapy closer to menopause than those initiating therapy more distant from menopause.
Women's Health Initiative Memory Study: The estrogen-alone Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 2947 predominantly healthy hysterectomized post-menopausal women 65 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) in the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for CE alone vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in both the treatment and placebo groups was AD. Since the substudy was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger post-menopausal women (see WHIM Study as previously mentioned and Dementia under Precautions).
Pharmacokinetics: Absorption: Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation. The CE tablet releases conjugated estrogens slowly over several hours. Maximum plasma concentrations are achieved approximately 6-10 hours following CE tablet administration. The estrogens are generally eliminated in near-parallel fashion, with half-lives ranging from 10-20 hours, when corrected for endogenous concentrations as needed.
Distribution: 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.
Metabolism: 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 gut followed by reabsorption. In post-menopausal 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.
Excretion: Estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.
Special Populations: No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.
Toxicology: Preclinical Safety Data: Not applicable.