Highlights Of Scientific Studies Related To Menopause Issues

July 12, 2011

Estrogen plus progestin therapy does not have a clinically significant effect on postmenopausal women's health-related quality of life, according to this analysis of data from the Women's Health Initiative (WHI), a randomized, double-blind, placebo-controlled trial.

The following news item from The North American Menopause Society (NAMS) contains commentary regarding data from the Women's Health Initiative on the effect estrogen-progestin therapy has on quality of life in postmenopausal women, as recently reported by The New England Journal of Medicine. Please note that the opinions expressed in the commentaries are those of the authors and are not necessarily endorsed by The North American Menopause Society.

Also note that the level of evidence indicated for each study is based on a grading system that evaluates the scientific rigor of the study design as developed by the US Preventive Services Task Force. A synopsis of the levels is presented at the end of these items.

Reprinted with permission of NAMS

QOL benefits lacking for long-term estrogen-progestin therapy in postmenopausal women
Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:[May 8 publication date].

Estrogen plus progestin therapy does not have a clinically significant effect on postmenopausal women's health-related quality of life, according to this analysis of data from the Women's Health Initiative (WHI), a randomized, double-blind, placebo-controlled trial. In the WHI, 16,608 postmenopausal women aged 50 to 79 years (mean age, 63) received either combined estrogen (0.625 mg/day conjugated equine estrogens) plus progestin (2.5 mg/day medroxyprogesterone acetate) or placebo. Quality-of-life (QOL) measures were collected in all study participants at baseline and after 1 year and then after 3 years in a subgroup of 1,511 women. At study end, estrogen-progestin therapy (EPT) users had no benefit over placebo recipients on any QOL outcomes, including general health, vitality, mental health, depressive symptoms, or sexual satisfactions. At 1 year, EPT use was associated with statistically significant, but not clinically significant, benefits in sleep disturbance (mean benefit, 0.4 point on a 20-point scale), physical functioning (mean benefit, 0.8 point on a 100-point scale), and body pain (mean benefit, 1.9 points on a 100-point scale). After 3 years, results were not significant. In a post hoc analysis of women aged 50 to 54 years with moderate to severe vasomotor symptoms, EPT improved vasomotor symptoms and resulted in a small benefit in sleep disturbance, but it provided no benefit in other QOL outcomes.
Level I evidenceComment. In this most recent analysis from the WHI, the finding of no significant clinical QOL benefit is comparable to that found in the Heart and Estrogen/progestin Replacement Study (HERS) [Hlatky JAMA 2002] where no improvement in QOL was seen in older postmenopausal women. In HERS, improvements in mental health and depressive symptoms were only found in women with hot flashes assigned to hormone therapy. When WHI investigators looked at symptomatic women, QOL results were still not significant. However, it is important to note that in the WHI study, women with significant vasomotor symptoms were dissuaded from entering the trial because of the possibility of receiving a placebo. In addition, women were asked to self-define moderate to severe hot flashes, relying on their memory to complete the questionnaires after 1 and 3 years. In contrast, in the Women's Health, Osteoporosis, Progestin and Estrogen (HOPE) study, [Utian Fertil Steril 2001] investigators used more strictly defined definitions of moderate to severe hot flashes. To be included in the analysis of moderate to severe category, the women had to record at least seven hot flashes per day for the last 7 days of screening or a total of 49 hot flashes over the 7 days. These differences in how data were obtained and the use of women's self-definitions rather than more strictly controlled definitions may be related to the high placebo effect in the WHI -- at the 1 year follow-up of the subgroup of women reporting moderate-severe vasomotor symptoms at baseline, placebo recipients had a 52% improvement in night sweat severity and 51.7% improvement in hot flash severity.

In conclusion, the WHI study found that in an older population of postmenopausal women using EPT primarily for prevention of heart disease, there were no clinically significant improvements in QOL. However, for women with menopause-related symptoms, this study does not answer the question of whether EPT improves QOL in women with moderate to severe symptoms. It also does not answer the question how important QOL benefit is to individual symptomatic women in comparison with the small increased risks reported previously from WHI of cardiac events, blood clots, stroke, gallbladder disease, and breast cancer.

JoAnn V. Pinkerton, MD
Associate Professor Ob/Gyn
Division Chief and Director Midlife Health Center
University of Virginia Health Sciences Center
Charlottesville, VA
Comment. The WHI Investigators report essentially that elderly women on continuous-combined estrogen and progestin demonstrated no improvement in health-related quality-of-life (QOL) compared with placebo. However, this study has substantial problems.

First, the study design was impaired because most of the study population were older and asymptomatic, not a general perimenopausal symptomatic population. Second, biomedical measures were used to assess QOL. While these measures are a necessary component to determine health status, they are not sufficient to accurately reflect a sense of global well being. As no validated QOL instrument was used, investigators had to rely on a series of surrogate tests to determine QOL, virtually all with severe limitations. For example, only one question was used to determine sexuality, a crude evaluation for cognitive benefit (the Modified Mini-Mental State Examination), and they used the RAND-36 Item Health Survey, which is designed to test more for health-related factors than for sense of well-being and QOL. Third, progestin is known to attenuate estrogenic effects, and this study involves the continuous administration of progestin with estrogen.

Investigators recognized these limitations and, thus, conducted a post hoc analysis to determine the impact of estrogen-progestin therapy on QOL in a subset of younger, symptomatic women -- a much more accurate subset to evaluate. However, this was based on an intent-to-treat analysis. Although this analysis may be satisfactory for determining disease prevention outcomes, such as breast cancer and heart disease, it is unacceptable when evaluating a mental benefit to include women not taking an active drug and then comment on a lack of effect from that drug.

In conclusion, while these results suggest that combined estrogen-progestin has a lack of effect on QOL in older asymptomatic women, they cannot be extrapolated to make a statement regarding the role of estrogen alone in enhancing overall QOL in symptomatic perimenopausal or early postmenopausal women.

Many studies attest to the negative impact of progestin in hormone therapy. Most women who discontinue hormone therapy do so because of progestin-related side effects, such as mood disturbances, uterine bleeding, and breast tenderness. In the medical literature, most enhanced QOL appears to be estrogen related. The lack of beneficial QOL in this study, therefore, could have been predicted. Perhaps the estrogen-only arm of the WHI will help clarify this effect, although it too will be compromised by lack of a validated QOL instrument.

Wulf H. Utian, MD, PhD
Arthur H. Bill Professor Emeritus of Reproductive Biology and Ob/Gyn
Case Western Reserve University School of Medicine
Consultant in Women's Health
Cleveland Clinic Foundation
Executive Director
The North American Menopause Society
Cleveland, OHDescription of the levels of evidence

Level I: Properly randomized, controlled trial.
Level II-1: Well-designed controlled trial but without randomization.
Level II-2. Well-designed cohort or case-control analytic study, preferably from more than one center or research group.
Level II-3: Multiple time series with or without the intervention (eg, cross-sectional and uncontrolled investigational studies); uncontrolled experiments with dramatic results could also be regarded as this type of evidence.
Level III: Opinions of respected authorities that are based on clinical experience; descriptive studies and case reports; reports from expert committees.

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