Estradiol and Norgestimate

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronised, oral 17β-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 μg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate).

According to data from randomised, comparative trials of 1 year’s duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells.

In a randomised, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in placebo-treated patients.

Two randomised, double-blind studies indicated that the addition of norgestimate 90 μg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels.

In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 μg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 μg/day was associated with a favourable uterine bleeding profile that improved over time. In a randomised trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 μg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day.

In conclusion, data from a limited number of randomised studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favourable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

This review concerns hormone replacement therapy (HRT) in the form of continuous administration of micronised, oral 17β-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 μg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate).

Animal studies have shown that progestogens inhibit the synthesis of their own receptors as well as estrogen receptors in the endometrium. By administering norgestimate in an intermittent manner, this inhibition is periodically removed. When norgestimate is withdrawn, the unopposed estrogen increases the number of estrogen and progestogen receptors. The target cells are thus resensitised to both these hormones, allowing a lower total dosage of norgestimate to be administered.

In two randomised trials in postmenopausal women, the addition of intermittent norgestimate 90 μg/day did not negate the beneficial effects of estradiol 1 mg/day on lipid and lipoprotein levels in postmenopausal women. Treatment with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with increases in mean serum high density lipoprotein (HDL)- (5 and 10%) and HDL₂- (24 and 29%) cholesterol and apolipoprotein A1 levels (7%) and decreases in total cholesterol (2 and 9%), low density lipoprotein (LDL)-cholesterol (5 and 15%) and lipoprotein (a) [11 and 31%], compared with baseline. Although triglyceride levels increased by 4 to 9%, this increase was not statistically significant compared with baseline.

Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day had a more beneficial effect on the lipid/lipoprotein profile than continuous oral estradiol 2 mg/day plus norethisterone acetate 1 mg/day in a randomised, doubleblind study.

Following multiple doses of continuous estradiol plus intermittent norgestimate, estradiol reached a peak serum concentration (C_max) of 46.2 ng/L after approximately 7 hours. The plasma elimination half-life (t½β) of estradiol is approximately 16 hours. Estradiol is metabolised in the liver to estrone, estriol and their conjugates. The metabolites are mainly excreted as sulphate and glucuronide conjugates in the urine, although some enterohepatic recirculation may occur. Norgestimate is extensively metabolised by first-pass mechanisms in the gastrointestinal tract and/or liver to 17-deacetylnorgestimate (norelgestromin). The C_maxof 17-deacetylnorgestimate of 643 ng/L was reached after 2 hours. The mean t½β of 17-deacetylnorgestimate was 37 hours. Norgestimate metabolites are eliminated in the urine or faeces.

In three randomised, 1-year studies, treatment with continuous estradiol 1 mg/ day plus intermittent norgestimate 90 μg/day was effective in eliminating climacteric symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day appeared as effective as continuous unopposed estradiol 1 mg/day or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms, with ≥70% of women free from symptoms at 3 to 4 months. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was as effective as continuous unopposed estradiol 1 mg/day in causing the maturation of vaginal epithelial cells.

In a randomised, double-blind study, bone mineral density increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in placebo-treated patients.

In a 12-month, randomised study, the incidence of breast discomfort, abdominal pain, oedema and dysmenorrhoea was lower in postmenopausal women treated with continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day than in women treated with continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day.

Randomised trials indicated that continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day was associated with a uterine bleeding profile that improved over time. In a combined analysis of two randomised, double-blind 1-year trials, 69, 71 and 80% of women were free from bleeding (irrespective of spotting) at 1, 6 and 12 months, respectively. In a randomised 1-year trial, continuous estradiol 1 mg/day plus intermittent norgestimate 90 μg/day had a bleeding profile that was similar to that of continuous oral estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day.

In a comparative trial in postmenopausal women, 90 μg/day was the minimal dosage of norgestimate that was required to protect postmenopausal women against induction of endometrial hyperplasia in a regimen of intermittent norgestimate and continuous estradiol 1 mg/day. Endometrial hyperplasia developed in 28% of women treated with continuous estradiol 1 mg/day alone, and in 6, 0 and 0% of women after the addition of intermittent norgestimate 30, 90 and 180 μg/day, respectively.

In the continuous estradiol plus intermittent norgestimate regimen, a single oral tablet containing estradiol 1mg is taken once daily for the first 3 days of therapy, and a different tablet containing estradiol 1mg plus norgestimate 90μg is taken once daily on days 3 to 6. This 6-day sequence is then repeated continuously.

Estradiol 1 mg/day plus intermittent norgestimate 90 μg/day is contraindicated in women with known or suspected pregnancy, undiagnosed abnormal genital bleeding, known or suspected cancer of the breast, known or suspected estrogen-dependent neoplasia, or active or past history of thrombophlebitis or thromboembolic disorders.