Estradiol Valerate/Medroxyprogesterone Acetate

Objective: To examine quality of life after a decade of continuous combined hormone replacement therapy. Study design: The 15D, a generic health-related quality-of-life (HRQoL) instrument, was used to evaluate trends in HRQoL in women who used continuous combined hormone replacement therapy (ccHRT; Indivina®, Orion Pharma, Finland) for up to nine years. These women had a mean age of 56 years of age at the start of therapy. Control data on HRQoL were obtained from age-matched women participating in Finnish population health surveys. Results: Relative to controls, ccHRT was associated with significantly better HRQoL after six and nine years of treatment. Dose minimization at 8.5 years was not associated with a decline in HRQoL in the ensuing six months. One year after discontinuation of ccHRT there was evidence of a decline in HRQoL in women who discontinued ccHRT as planned, whereas HRQoL was maintained in women who had continued or resumed ccHRT during the one-year post-study follow-up. The benefits of ccHRT were apparent in multiple dimensions of the 15D, being largest and most robustly reproduced in the dimension 'discomfort and symptoms'. It is conjectured that the effectiveness of ccHRT in relieving symptoms of menopause may have contributed to the improved HRQoL scores registered in other dimensions, in addition to any direct effects of ccHRT on specific aspects of those other dimensions. Conclusions: These data indicate that up to 10 years of low-dose ccHRT has sustained value in the enhancement of HRQoL when used by women for whom relief of symptoms of menopause and control of bleeding are primary objectives of treatment.

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.

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.

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%.

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.