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.

Norgestimate is a derivative of 19-nortestosterone and binds to androgen and progestogen receptors, similar to that of the natural hormone progesterone; it does not bind to estrogen receptors. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics

Absorption

Estradiol reaches its peak serum concentration (Cmax) at approximately 7 hours in postmenopausal women receiving PREFEST (estradiol, norgestimate) (Table 1). Norgestimate is completely metabolized; its primary active metabolite, 17-deacetylnorgestimate, reaches Cmax at approximately 2 hours after dose (Table 1). Upon co-administration of PREFEST (estradiol, norgestimate) with a high fat meal, the Cmax values for estrone and estrone sulfate were increased by 14% and 24%, respectively, and the Cmax for 17-deacetylnorgestimate was decreased by 16%. The AUC values for these analytes were not significantly affected by food.

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 concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. 17-deacetylnorgestimate, the primary active metabolite of norgestimate, does not bind to SHBG, but to other serum proteins. The percent protein binding of 17-deacetylnorgestimate is approximately 99%.

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 postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is 17-deacetylnorgestimate.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norgestimate metabolites are eliminated in the urine and feces. The half-life (t_1/2) of estradiol and 17-deacetylnorgestimate in postmenopausal women receiving PREFEST (estradiol, norgestimate) is approximately 16 and 37 hours, respectively.

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.

Results of a subset population (n=24) from a clinical study conducted in 36 healthy postmenopausal women indicated that the steady state serum estradiol levels during the estradiol plus norgestimate phase of the regimen may be lower by 12-18% as compared with estradiol administered alone. The serum estrone levels may decrease by 4% and the serum estrone sulfate levels may increase by 17% during the estradiol plus norgestimate phase as compared with estradiol administered alone. The clinical relevance of these observations is unknown.

Special Populations

Race and body weight

The effects of race and body weight on the pharmacokinetics of estradiol, norgestimate, and their metabolites were evaluated in 164 healthy postmenopausal women (100 Caucasians, 61 Hispanics, 2 Blacks, and 1 Asian). No significant pharmacokinetic difference was observed between the Caucasian and the Hispanic postmenopausal women. No significant difference due to body weight was observed in women in the 60 to 80 kg weight range. Women with body weight higher than 80 kg, however, had approximately 40% lower peak serum levels of 17-deacetylnorgestimate, 30% lower AUC values for 17-deacetylnorgestimate and 30% lower Cmax values for norgestrel. The clinical relevance of these observations is unknown.

No pharmacokinetic studies were conducted in other special populations.

Table 1. MEAN PHARMACOKINETIC PARAMETERS OF E₂, E₁, E₁S, AND 17d-NGM¹ FOLLOWING SINGLE AND MULTIPLE DOSING OF PREFEST (estradiol, norgestimate)

Clinical Studies

Effects on vasomotor symptoms

The effect of the estrogen component of PREFEST (estradiol, norgestimate) on vasomotor symptoms was confirmed in a 12-week placebo-controlled trial of 168 healthy postmenopausal women between 28 and 66 years of age (87% Caucasian) with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the PREFEST (estradiol, norgestimate) regimen) was studied in two 12-month trials in 1212 healthy postmenopausal women between 40 and 65 years of age (85% Caucasian) for endometrial protection. Results from a subset population (n=119) of these 12-month trials (women with MSVS) are shown in Table 2.

Table 2. CHANGE IN THE MEAN NUMBER OF MODERATE TO SEVERE VASOMOTOR SYMPTOMS (SUBSET OF SUBJECTS WITH 7 OR MORE MODERATE TO SEVERE HOT FLUSHES PER DAY)

The effects of the addition of norgestimate on steady state estrogen levels and the clinical relevance thereof have been discussed in CLINICAL PHARMACOLOGY (see DRUG INTERACTIONS).

Effects on vulvar and vaginal atrophy

The effect of the estrogen component of PREFEST (estradiol, norgestimate) on vulvar and vaginal atrophy was confirmed in a 12-week placebo-controlled trial of healthy postmenopausal women with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the PREFEST (estradiol, norgestimate) regimen) was studied in a 12-month trial in 143 healthy postmenopausal women between 42 and 65 years of age (92% Caucasian) for endometrial protection. Results from a subset population (n=69) with paired tests for maturation index of the vaginal mucosa are shown in Table 3.

Table 3. SUMMARY OF MATURATION INDEX RESULTS IN SUBJECTS WITH PAIRED TESTS FOLLOWING 7 MONTHS TREATMENT WITH PREFEST (estradiol, norgestimate) OR ESTRADIOL

Effects on the endometrium

The effect of PREFEST (estradiol, norgestimate) on the endometrium was evaluated in two 12-month trials. The combined results are shown in Table 4.

Table 4. INCIDENCE OF ENDOMETRIAL HYPERPLASIA AFTER 12 MONTHS OF TREATMENT (INTENT TO TREAT POPULATION)

In another 12-month controlled clinical trial for endometrial protection an additional 190 postmenopausal women were treated with PREFEST (estradiol, norgestimate) . No subject had a diagnosis of endometrial hyperplasia after treatment.

Effects on uterine bleeding or spotting

The effects of PREFEST (estradiol, norgestimate) on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in two 12-month trials. Combined results are shown in Figure 1.

Figure 1: Subjects with Cumulative Amenorrhea Over Time (Percentage of Women With No Bleeding or Spotting At a Given Month Through Month 12), Intent to treat Population

Effects on lipids

The effect of PREFEST (estradiol, norgestimate) on lipids was evaluated in a 12-month metabolic trial of healthy postmenopausal women.

Table 5. EFFECTS ON LIPOPROTEINS AT MONTH 12

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 oral 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 6 below:

Table 6. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI^a

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 WARNING, 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 WARNING and WARNINGS, Dementia.)

Last reviewed on RxList: 3/4/2009
This monograph has been modified to include the generic and brand name in many instances.