Hormone Therapy May Improve Symptoms Even if Started Many Years After Menopause
Combined hormone replacement therapy (HRT) started many years after menopause can improve some aspects of health-related quality of life, according to the results of a randomized, placebo-controlled, double-blind trial reported in the August 21 Online First issue of the BMJ.
“There is debate about the effect of…HRT on health related quality of life, though it has been shown to improve general quality of life through the reduction of both the number and severity of menopausal symptoms,” write Amanda J. Welton, from MRC General Practice Research Framework, Stephenson House in London, United Kingdom, and colleagues from the women’s international study of long duration oestrogen after the menopause (WISDOM) team.
At 384 general practices in the United Kingdom, 94 in Australia and 24 in New Zealand, 3721 postmenopausal women with a uterus who were 50 to 69 years old were randomly assigned to receive conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg (n = 1862) or matched placebo (n = 1859) orally daily. At 1 year, data on health-related quality of life were available from 1043 and 1087 women, respectively.
Primary endpoints were health-related quality of life and psychological well-being based on the women’s health questionnaire, changes in emotional and physical menopausal symptoms based on a symptoms questionnaire, and depression measured by the Centre for Epidemiological Studies depression scale. In addition, overall health-related quality of life was measured with the European quality-of-life instrument, and overall quality of life was measured with the visual analog scale.
Compared with women assigned to placebo, those assigned to combined HRT had small but significant improvements after 1 year in 3 of 9 components of the women’s health questionnaire: vasomotor symptoms (P < .001), sexual functioning (P < .001), and sleep problems (P < .001). The combined HRT group also fared better than the placebo group in the number of women reporting hot flushes (P < .001), night sweats (P <.001), joint and muscle aches (P = .001), insomnia (P < .001), and vaginal dryness (P < .001). However, more women in the combined HRT group vs the placebo group reported breast tenderness (P < .001) or vaginal discharge (P < .001).
At trial entry, 30% in the combined HRT group and 29% in the placebo group had hot flushes; at 1 year, the corresponding percentages were 9% and 25%, respectively. At 1 year, there were no significant differences in other menopausal symptoms, depression, or overall quality of life.
“Combined HRT started many years after the menopause can improve health related quality of life,” the study authors write.
Limitations of this study include loss to follow-up and discontinuation of study medication, particularly in the combined HRT group, introducing selection bias; premature closure of the trial causing exclusion of approximately 36% of women in both treatment groups; insufficient power to determine whether the effect differs in those who keep taking HRT and those who stop; and relatively short duration of follow-up.
“The results of WISDOM are clinically relevant for doctors treating postmenopausal women with relevant symptoms including vasomotor symptoms, sleep disturbance, and aching joints and muscles,” the study authors conclude. “When women start combined HRT many years after the menopause they must balance the risk of increased cardiac events, venous thromboembolism, and breast cancer against possible benefits on health related quality of life. They must also consider possible early side effects of combined HRT such as breast tenderness, vaginal discharge, and uterine bleeding, which usually resolve with time or dose titration.”
Clinical Context
There is debate about the effect of HRT on health-related quality of life. Previous studies have suggested that HRT improves various symptoms of menopause and overall quality of life.
This is a study from WISDOM, an international, general-practice–based randomized clinical trial of HRT in postmenopausal women with an intact uterus. The trial was originally planned for 10 years of follow-up but was terminated prematurely at 1 year because of findings of the Women’s Health Initiative. This study examines outcomes of symptoms and quality of life at 1 year after the trial, after premature termination.
Study Highlights
* The study recruited 22,300 women from general practices in the United Kingdom, New Zealand, and Australia who were randomly assigned to receive HRT or placebo for 10 years, with recruitment from 1999 to 2002.
* Included were postmenopausal women aged 50 to 69 years with an intact uterus or subtotal hysterectomy.
* Women were randomly assigned to receive either combined HRT consisting of 0.625 mg of estrogen with oral medroxyprogesterone acetate 2.5/5.0 mg daily (n = 1862) or placebo (n = 1859).
* Scheduled visits were planned for baseline, 4, 14, 27, 40, and 52 weeks and annually thereafter.
* The study was closed early because of findings of the Women’s Health Initiative, with a median follow-up time of 1 year.
* This study is limited to data collected 1 year after randomization on health-related quality of life because data were available on less than half of participants at 2 years.
* The prevalence of individual symptoms was assessed with a 28-item symptom questionnaire asking about symptoms within the past 4 weeks.
* Depression was assessed with the Center for Epidemiological Studies depression scale, a 20-item self-report scale.
* The women’s health questionnaire was used to assess emotional and physical well-being with use of a modified version with 8 components (depressed mood, somatic symptoms, memory and concentration, vasomotor symptoms, anxiety and fears, sleep problems, and menstrual symptoms) assessed on a binary scale.
* The European quality-of-life instrument was used to determine quality of life with a visual analog scale and health classification index.
* Mean age at randomization was 63.8 years, and median time between baseline and 1-year interview was 368 days.
* At the 1-year interview, 28% in the HRT group and 13% in the placebo group were no longer taking the assigned medication.
* Those who stopped HRT did so mainly because of symptoms of vaginal bleeding or breast tenderness.
* The HRT group experienced significant improvements in vasomotor symptoms vs the placebo group at 1 year, and treatment differences were more marked for those with more severe baseline symptoms.
* Participants reported small but significant improvements in sexual functioning and sleep problems.
* Sexual function at 1 year was not associated with baseline vasomotor symptoms.
* The HRT group experienced fewer vasomotor symptoms including hot flushes (9% vs 25%; P < .001) and night sweats (14% vs 23%; P < .001).
* They were also less likely to report aching joints and muscles (57% vs 63%; P < .001), insomnia (35% vs 41%; P < .001), and vaginal dryness (14% vs 19%).
* The combined HRT group reported higher rates of breast tenderness (16% vs 7%; P < .001) and vaginal discharge (14% vs 5%; P < .001) vs the placebo group.
* There was no interaction for aching joints and muscles, insomnia, vaginal dryness, breast tenderness, or vaginal discharge.
* There was no significant difference in the scores of the Centre for Epidemiological Studies depression scale or self-assessed health as measured by the visual analog scale for the European quality-of-life instrument or the generic European quality-of-life instrument.
* The authors concluded that combined HRT was associated with improved individual symptoms but not with improved overall quality-of-life measures in postmenopausal women.
Pearls for Practice
* Combined HRT for 1 year in postmenopausal women is associated with reduced vasomotor symptoms, reduced vaginal dryness, and improved sexual functioning and sleep problems but increased breast tenderness and vaginal discharge.
* Use of combined HRT for 1 year in postmenopausal women is not significantly associated with improved overall health-related quality of life but did improve specific individual symptoms.
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