This 8-week placebo controlled trial enrolled 339 peri- and postmenopausal women aged 40 to 62 years from three USA clinical sites from November 2011 to October 2012 «Caan B, LaCroix AZ, Joffe H, ym. Effects of estrog...»1. Women were eligible for the study if they were in generally good health, were in the menopausal transition or postmenopausal, and reported 14 or more hot flashes/night sweats per week (recorded on daily diaries for 3 weeks) rated as bothersome or severe at least four times per week.
The primary trial outcome was frequency of vasomotor symptoms (VMS) at 8 weeks. Secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and from measures of pain (Pain, Enjoyment in life, and General activity scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder Questionnaire-7), and perceived stress (Perceived Stress Scale).
Women were randomized to low-dose oral 17β-E2 0.5 mg/day and venlafaxine XR 75 mg/day, versus identical placebo.
Treatment with both E2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E2: mean difference at 8 wk, −0.4; 95% CI, −0.7 to −0.2; P < 0.001; venlafaxine: mean difference at 8 wk, −0.2; 95% CI, −0.5 to 0.0; P = 0.04). Quality-of-life domain analyses revealed that E2 had beneficial treatment effects on all domains of the MENQOL except for the psychosocial domain, whereas venlafaxine benefits were observed only in the psychosocial domain. Neither E2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.
In all, 3721 postmenopausal women aged 50-69 (mean age 63.8 years (SD 4.4) with an intact uterus or subtotal hysterectomy had been randomised, 1862 to combined menopausal hormone therapy (MHT) (conjugated equine oestrogen (CEE) 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg) or matched placebo (n=1859) orally daily for one year. The study «Welton AJ, Vickers MR, Kim J, ym. Health related q...»2 was performed bygeneral practices in United Kingdom (384), Australia (94), and New Zealand (24).
Health related quality of life and psychological wellbeing as measured by the women's health questionnaire. Changes in emotional and physical menopausal symptoms were measured by a symptoms questionnaire and depression by the Centre for Epidemiological Studies depression scale (CES-D). Overall health related quality of life and overall quality of life as measured by the European quality of life instrument (EuroQol) and visual analogue scale, respectively.
After one year small but significant improvements were observed in three of nine components of the women's health questionnaire for those taking combined MHT compared with those taking placebo: vasomotor symptoms 0.09 (95% CI 0.07 to 0.12,P<0.001), sexual functioning (0.05 (95%CI 0.02 to 0.08;P<0.001), and sleep problems 0.05 (95% CI 0.02 to 0.07) (P<0.001). Significantly fewer women in the combined MHT group reported hot flushes (−15 (95% CI −18 to −12) ;P<0.001), night sweats (−9 (95% CI −13 to −6) ;P<0.001), aching joints and muscles (−7 (−11 to −2) P=0.001), insomnia (−6 (95%CI−10 to −2); P<0.001), and vaginal dryness (−5 (95%CI−8 to −2) P<0.001) than in the placebo group, but greater proportions reported breast tenderness (P<0.001) or vaginal discharge (9 (95%CI 7 to 12) ;P<0.001). Hot flushes were experienced in the combined HRT and placebo groups by 30% and 29% at trial entry and 9% and 25% at one year, respectively. No significant differences in other menopausal symptoms, depression, or overall quality of life were observed at one year.
Comment: CEE is not in use in Finland. The age of the study population was higher than the average age when MHT start is usually recommended.
A total of 419 Finnish women with uterus (mean age 56.2 (+2.00) years, age range 45-65 years), at least three years postmenopausal, BMI<30 kg/m2, were basically randomized to prospective single site, double -blind phase II dose-finding study for seven years to one of six treatment regiments (n=70 /each group): once-daily 1 mg estradiol valerate (E2V)/2.5 mg medroxyprogesterone acetate (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) «Heikkinen JE, Vaheri RT, Ahomäki SM, ym. Optimizin...»3.
In all, 198 women continued after year 7, when the treatment schedule was streamlined to three dose schedules: 1 mg E2V + 2.5 mg MPA (n=59); 1 mg E2V + 5 mg MPA (n=47); or 2 mg E2V + 5 mg MPA (n=92). The study was continued until 9 years. The 2 + 2.5 dosage was discontinued at the end of year 7 (manufacture of this product had stopped). For the last six months, all received the 1 + 2.5 dosage following 12 months follow up without MHT «Heikkinen J, Vaheri R, Timonen U. A 10-year follow...»4.
Altogather 279 women started the treatment with the three marketed doses (1/ 2.5 mg, 1/ 5mg and 2/ 5 mg). In all, 198 (71%) continued in the study after year 7, and 180 (65%) completed nine years of continuous combined menopausal hormone therapy (ccMHT).
Patients who had continued with either of the higher doses (1/5 or 2/5 mg) to 102 months (8.5 years) were recalled and invited to switch to the low-dose preparation to E2V1mg+MPA 2.5 mg for the remaining six months of the trial in all 9 years of therapy. The 10-year follow up was 12 months after discontinuation of ccMHT.
QOL
The HRQOL was measured after six years cross-sectionally with NHP (Nottingham Health Profile) and 15D instrument which was used at 6, 8.5, 9 and 10 years.
The 15D general population control data were obtained from age-matched women (both MHT users and non-users) from randomly recruited participants of two Finnish health-care surveys, which also used the 15D instrument to measure HRQoL. There were 257controls from the Finnish health-care survey for the six-year comparison, and 771 controls from the Finnish ‘Health2000' survey for the nine -year comparison «Ylikangas S, Sintonen H, Heikkinen J. Decade-long ...»5, «Sintonen H, Johansson S, Ohinmaa A, ym. Measuring ...»6.
In addition, Raitasalo–Beck Depression Inventory, The Sexual Life Index and modified Working Capacity Index were administered annually. Additionally, from year 7 and at the one-year follow-up, patients completed the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the Arizona Sexual Experience Scale (ASEX).
Results:
Raitasalo-Beck Depression inventory: The degree of depressive mood, degree of anxiety, perception of health and interest in sex all improved in all women from baseline to year 1 and this was maintained until year 9. At the one-year follow-up 83 women (47.2%) had experienced a recurrence of climacteric symptoms.
Sexual Life Index: at baseline, 75% of women had either a decreased interest or loss of interest in sex. With ccMHT, a significant improvement was observed from baseline to year 1 and at all subsequent assessments up to year 9 (mean change to year 9: –2.57, 95% CI –3.66 to –1.49; P < 0.0001).
Working Capacity Index: was essentially unchanged from baseline throughout the study; slight non-significant changes were apparent from baseline to the end of year 9.
Q-LES-Q: total score was maintained or improved from year 7 to year 9 in all women and in all groups. After discontinuation of ccMHT, there was an overall deterioration (mean decrease –2.3, SD 9.15), with significant deterioration of all individual item scores except sexual interest. The changes resulted primarily from a significant deterioration for women who did not use ccMHT during the follow-up (P = 0.0003).
ASEX: Women treated with the 1 + 2.5 dosage had the best (lowest) ASEX score while on ccMHT, both at year 7 and at year 9. The mean scores at year 9 were 21.3 (SD 5.8), 23.3 (SD 5.9) and 22.9 (SD 5.4) for the 1 + 2.5, 1 + 5, and 2 + 5 groups, respectively, and 22.5 (SD 5.7) for all women in the study after year 7. There was little change in ASEX score following discontinuation of ccMHT. At years 7, 8 and 9, the percentages of women with a sex life that was generally satisfactory (extremely, very or somewhat satisfactory categories) were 80%, 83% and 81%, respectively, compared with 83% at the one-year follow-up. A deterioration in ASEX score from the end of year 9 to the one-year follow- up (mean 3.0%, SD 13.3) was not statistically significant and was similar regardless of study dosage group or MHT use during follow-up. Also, for women not treated with MHT during follow-up, there was no difference between ASEX findings for those with a regular partner (60%) compared with all women.
15D: At year six the 15D score representing the overall HRQOL was statistically significantly higher in women using E2V/MPA (0.917) vs. controls (0.873) (p<0.05). The difference in scores was 0.044. The difference of 0.02-0.03 has been shown to be clinically significant while the subject can feel the difference. In all 13 out of 15 dimensions of 15 D, significant differences (p<0.05) in favour E2V/ MPA were shown in mobility, vision, breathing, sleeping, eating, elimination, usual activities, mental function, discomfort and symptoms, depression, distress, vitality and sexual activity.
With NHP women taking E2V/MPA had statistically significantly better HRQOL in every 6 dimensions eg. energy, sleep, pain, emotional reactions, social isolation, physical mobility «Sintonen H, Johansson S, Ohinmaa A, ym. Measuring ...»6.
In 9 years the mean 15D score among the study participants was 0.930 (95% CI 0.921 to 0.940) compared with 0.889 (0.883 to 0.896) in the controls, a clinically important difference in favour of cc MHT of 0.041 (P < 0.001) «Ylikangas S, Sintonen H, Heikkinen J. Decade-long ...»5.
Comment: Complicated study design. E2V/MPA is widely used in Finland.
A total of 150 postmenopausal women (mean age, 53.2 [0.2] y; time since menopause, 19.5 [0.8] months) were interviewed about hot flashes and health-related quality of life using the Women's Health Questionnaire and the McCoy Female Sexuality Questionnaire, menopause-related symptoms, and general health «Savolainen-Peltonen H, Hautamäki H, Tuomikoski P, ...»7. The women were classified into those with (n = 72) and without (n = 78) hot flashes and treated for 6 months with transdermal estradiol (1 mg/d), oral estradiol (2 mg/d) with or without medroxyprogesterone acetate (5 mg/d), or placebo (PO).
At baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = −0.525, P < 0.0001), muscle pains (r = −0.348, P < 0.0001), menstrual cycle–resembling complaints (r = −0.304, P < 0.0001), anxiety and fears (r = −0.283, P < 0.0001), decreased memory and concentration (r = −0.279, P = 0.001), and sexual behaviour (r = −0.174, P = 0.035).
The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group (MHT) for further analysis.
In women with baseline flashes, six month use significantly improved the scores for sleep (MHT; 0.787 [0.243] vs PO; 0.557 [0.249], P = 0.001), memory and concentration capacity (MHT; 0.849 [0.228] vs PO; 0.454 [0.301], P < 0.0001), and anxiety and fears (MHT; 0.942 [0.133] vs PO; 0.826 [0.193], P = 0.005). MHT showed no significant impact on these variables in women without baseline flashes.