A 10-year follow-up of postmenopausal women on long-term continuous combined hormone replacement therapy: Update of safety and quality-of-life findings.

OBJECTIVE: To assess the safety and health-related quality of life (HRQOL) of continuous combined hormone replacement therapy (ccHRT) with estradiol valerate/medroxyprogesterone acetate (E(2)V/MPA) over nine years and at follow-up one year after discontinuation. STUDY DESIGN: A total of 419 women were randomized to one of four treatments: once-daily 1 mg E2V/2.5 mg MPA (1 + 2.5 group); 1 mg E2V/5 mg MPA daily (1 + 5 group); 2 mg E2V/2.5 mg MPA daily (2 + 2.5 group); 2 mg E2V/5 mg MPA daily (2 + 5 group) (Indivina, Orion Pharma). For the last six months, all received the 1 + 2.5 dosage. The 2 + 2.5 dosage was discontinued at the end of year 7. A total of 198 women continued after year 7. RESULTS: Annualized percentage rates for cardiovascular events [corrected] and endometrial cancers [corrected] were below national rates for Finland and those reported for the Women's Health Initiative. There were no serious events with the 1 + 2.5 dosage or after ccHRT discontinuation. Climacteric symptoms remained significantly below baseline values after dosage reduction; some symptoms recurred after discontinuation of ccHRT. HRQOL ratings improved with ccHRT, irrespective of dosage, including depressed mood, anxiety, health perception and sexual interest. Scores on a scale assessing daily functioning and enjoyment (Q-LES-Q) improved from year 7 to year 9. They deteriorated during follow-up in women not continuing ccHRT. CONCLUSIONS: Lower dosages of HRT were as effective as higher doses in improving climacteric symptoms and HRQOL ratings and had fewer safety concerns. Following discontinuation of ccHRT, patient satisfaction was variable, with 15% electing to continue or restart HRT and 7% resuming at follow-up. This supports the need for an individualized approach to therapy recommendations.

Long-term safety and tolerability of continuous-combined hormone therapy in postmenopausal women: results from a seven-year randomised comparison of low and standard doses.

OBJECTIVE: To establish the long-term safety profile of four oestradiol valerate/medroxyprogesterone acetate (E(2)V/MPA) regimens. STUDY DESIGN: 419 postmenopausal women in parallel treatment groups started treatment with 1 or 2 mg E(2)V with either 2.5 or 5 mg MPA for 84 cycles of 28 days in a randomised, comparative study. The first 24 month double-blind efficacy period has been previously reported. This report focuses on the open safety period after the first two years until completion of 84 treatment cycles. RESULTS: A total of 275 women (65.6%) completed the seven-year study. All regimens provided good bleeding control and endometrial protection, with no cases of endometrial hyperplasia or cancer diagnosed. All regimens were well tolerated with a low frequency of adverse effects, mostly occurring within the first two years. The most common drug-related adverse events included breakthrough bleeding, headache/migraine, abdominal pain and mood changes. Very few women (n = 4) receiving the lowest dose option (1 mg E(2)V + 2.5 mg MPA) reported adverse effects (p<0.009 vs other groups). No serious cardiovascular events occurred in any of the groups, the incidence of strokes was lower than the national incidence for the age group and the incidence of breast cancer was comparable with the national incidence (95% CI). In the lowest dose group, no women had to stop therapy prematurely due to serious adverse events. CONCLUSIONS: The results support the use of lower doses for longterm hormone therapies.

A 10-year follow-up of the effect of continuous-combined hormone replacement therapy and its discontinuation on bone in postmenopausal women.

OBJECTIVE: To establish the effect on bone mineral density (BMD) of long-term (nine years) continuous-combined hormone replacement therapy (ccHRT) with estradiol valerate/medroxyprogesterone acetate (E(2)V/MPA) and follow-up one year after discontinuation of ccHRT. STUDY DESIGN: A total of 279 women were treated with daily dosages of E(2)V + MPA: 1 mg + 2.5 mg (n = 69), 1 mg + 5 mg (n = 70) or 2 mg + 5 mg (n = 140) (Indivina), Orion Pharma, Espoo, Finland) for 8.5 years; all subjects received the lowest dosage for the next six months. BMD was measured at baseline, between 6 and 12 months, annually until the end of study and at one-year postdiscontinuation of ccHRT. Main outcome measure Change in BMD during nine years of treatment with ccHRT and at one-year postdiscontinuation of ccHRT. RESULTS: Progressive increase of vertebral BMD was observed with all dosage regimens throughout nine years, with corresponding reduction in the proportion of women fulfilling criteria for osteoporosis or osteopaenia. Femoral neck BMD reached a peak at about five to six years, whereas in the lumbar spine the BMD increase was sustained until the end of the study treatment. Mean BMD declined after cessation of ccHRT use but remained substantially above baseline levels. In a subset of women (n = 58) there was a rapid (> or =4%) loss of vertebral BMD in the year after termination of ccHRT use. These women had lower than average BMD at baseline but no other factor was identified that distinguished them from the overall study population. CONCLUSIONS: Low-dose ccHRT in postmenopausal women is associated with increases in lumbar spine BMD for at least nine years. These gains are not sustained after cessation of therapy but the rate of BMD loss varies between individuals.