Endometrial safety and tolerability of triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate therapy regimen

Abstract

Objective Two randomized comparative multicenter studies were conducted to establish the endometrial safety and tolerability of a triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate (E₂V/MPA) therapy regimen.

Methods Study 1 was a randomized, double-blind, clinical phase III study in 399 postmenopausal women, following parallel-group design with two groups. The duration of study treatment was 12 or 13 cycles of 28 days. A double-dummy technique was used to ensure blinding in the study. The investigational drugs were E₂V/MPA triphasic and E₂V/MPA biphasic (Diviseq^® and Divina^®, respectively; Orion Pharma).

In study 2, a total of 341 subjects were randomly allocated by computer into two parallel groups receiving either E₂V/MPA or estradiol/norethisterone acetate triphasic (E₂/NETA, Trisequens?; Novo Nordisk A/S) for 12–13 cycles. The study was an open, clinical phase III trial with a randomized, parallel-group design.

Endometrial biopsies combined with transvaginal ultrasound were undertaken before and at the end of treatment during the progestogen phase. Bleeding patterns and symptom control were assessed throughout both studies.

Results E₂V/MPA triphasic was found to have similar endometrial effects and bleeding patterns to those with E₂V/MPA biphasic and E₂/NETA triphasic. Climacteric symptoms were relieved as quickly and effectively as with the two comparator treatments. No adverse drug reactions specific to E₂V/MPA triphasic were observed. At the end of the study, the proportions of secretory samples were 67.1% for the combined E₂V/MPA triphasic groups, 65.6% for the E₂V/MPA biphasic group and 71.6% for the E₂/NETA triphasic group. One case of hyperplasia occurred in the E₂V/MPA triphasic group. Thus the incidence of hyperplasia for the combined groups was 0.33%.

Conclusions The triphasic E₂V/MPA regimen was well tolerated and produced endometrial effects similar to those of the two comparators. Extending estrogen during the so-called treatment-free week with a lower dose of estradiol was effective in controlling vasomotor symptoms.

• ESTRADIOL VALERATE
• MEDROXYPROGESTERONE ACETATE
• TRIPHASIC
• BIPHASIC
• NORETHISTERONE
• HORMONE REPLACEMENT
• MENOPAUSE