Menopause: The Journal of The North American Menopause Society Vol. 21, No. 7, pp. 732/739 DOI: 10.1097/gme.0000000000000120 * 2013 by The North American Menopause Society
Health-related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy Hanna Savolainen-Peltonen, MD, PhD,1,2 Hanna Hautama¨ki, MD,1 Pauliina Tuomikoski, MD, PhD,1 Olavi Ylikorkala, MD, PhD,1 and Tomi S. Mikkola, MD, PhD1,2 Abstract Objective: We assessed the impact of hot flashes and various forms of hormone therapy on health-related quality of life and sexual well-being in recently postmenopausal women. Methods: We prospectively interviewed 150 healthy women about hot flashes and health-related quality of life (using the Women’s Health Questionnaire and the McCoy Female Sexuality Questionnaire), menopauserelated symptoms, and general health. 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. Results: At baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = j0.525, P G 0.0001), somatic symptoms such as muscle pains (r = j0.348, P G 0.0001), menstrual cycleYresembling complaints (r = j0.304, P G 0.0001), anxiety and fears (r = j0.283, P G 0.0001), decreased memory and concentration (r = j0.279, P = 0.001), and sexual behavior (r = j0.174, P = 0.035). The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group for further analysis. In women with baseline flashes, hormone therapy use significantly improved the scores for sleep (0.787 [0.243] vs 0.557 [0.249], hormone therapy vs placebo, P = 0.001, at 6 mo), memory and concentration capacity (0.849 [0.228] vs 0.454 [0.301], P G 0.0001, at 6 mo), and anxiety and fears (0.942 [0.133] vs 0.826 [0.193], P = 0.005, at 6 mo). Hormone therapy use showed no significant impact on these variables in women without baseline flashes. Conclusions: Hot flashes contribute differently to various variables affecting health-related quality of life shortly after menopause. Estradiol or an estradiolYmedroxyprogesterone acetate combination similarly alleviates hot flashes and improves health-related quality of life in relation to elimination of hot flashes. Hormone therapy use does not confer any detectable quality-of-life benefit over placebo in women without disturbing baseline flashes. Key Words: Menopause Y Hot flashes Y Quality of life Y Hormone therapy.
F
ifty percent to 80% of women complain about menopausal symptoms such as hot flashes, night sweats, sleep disturbances, tiredness, and depressive mood. They are the principal determinants of a reduced health-related quality of life (HRQL), which is detectable quite soon after the onset of menopause.1 It is a common belief that hot flashes (originating from hypothalamic dysregulation of thermal centers as a consequence of reduced estrogen levels) would be the primary sign of menopause, and that other mental or somatic
Received July 7, 2013; revised and accepted September 5, 2013. From the 1Department of Obstetrics and Gynecology, Helsinki University Central Hospital and the University of Helsinki, Helsinki, Finland; and 2Folkha¨lsan Research Institute, Helsinki, Finland. Funding/support: This study was supported by a Helsinki University Central Hospital research grant, the Finnish Medical Foundation, the Foundation of Paulo, the Finnish Menopause Society, and the Jalmari and Rauha Ahokas Foundation. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Tomi S. Mikkola, MD, PhD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, PO Box 140, Helsinki FIN-00029 HUS, Finland. E-mail: [email protected]
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symptoms would only be secondary phenomena to hot flashes. However, in view of the profound effects of estrogen on, for example, neural cells and connective tissues, the secondary characters of many nonflash symptoms can be questioned.2,3 The delineation between flashes and nonflash symptoms in clinical research is difficult. First, severe hot flashes, with or without night sweats, are often so dominant that they override the other symptoms. Second, women show marked differences in their capacity to tolerate hot flashes; some are disturbed by flashes that are readily acceptable by others.4 A woman may not be totally unbiased while judging her hot flashes; undue negative coverage of hormone therapy (HT) by the media has influenced some women to BtolerateB even rather severe symptoms to avoid the initiation of HT. Third, hot flashes show marked day-to-day or even hour-to-hour variations; therefore, their reliable assessment is prone to large interindividual and intraindividual fluctuations. Preferably, hot flashes should be assessed prospectively with interview tools, which aim to be maximally objective5,6; this was not the case in many previous quality-of-life trials.7,8 Generally, only women with intolerable hot flashes are considered as candidates for HT.
Menopause, Vol. 21, No. 7, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
IMPACT OF HOT FLASHES ON QUALITY OF LIFE
FIG. 1. Flow chart of the study showing the impact of hot flashes on health-related quality of life.
Oral or transdermal estrogen is a drug of choice for hot flashes and other menopausal symptoms. Estrogen-only therapy is applicable for hysterectomized women, whereas nonhysterectomized women must combine estrogen with a progestin for endometrial protection. Progestin may, however, oppose or even eliminate the positive effects of estrogen.9,10 In this regard, medroxyprogesterone acetate (MPA), which was combined with conjugated equine estrogens in the Women’s Health Initiative trial,8 has been most discussed because MPA may worsen cognitive function.11 The effect of different hormonal regimens on HRQL is poorly understood. We analyzed the impact of hot flashes on HRQL, general health, and sexual well-being within the first 6 to 36 months after menopause. The women were classified into those with or without hot flashes and treated with transdermal or oral HT, with or without MPA, in a randomized placebo-controlled trial for 6 months to see how the treatments affect life quality variables in these women. METHODS Study population A total of 150 postmenopausal women (mean [SD] age, 53.2 [0.2] y; mean [SD] time since menopause, 19.5 [0.8] mo) were included in the trial, as reported previously.12 The women received oral and written information about the study, and they all agreed to take part in the forthcoming HT trial regardless of their symptoms. This study was approved by the Helsinki University Women’s Hospital ethics committee and registered with the National Agency for Medicine (EudraCT 2004-005091-16) and the US National Institutes of Health Clinical Registry (NCT00668603). The study was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki.
Menopausal symptoms Women were interviewed with a structured questionnaire for 19 leading menopausal symptoms (eg, insomnia, depressive mood, nervousness, aching joints or muscles, or vaginal dryness) occurring in the past 2 weeks. The incidence of the symptoms was scored as follows: 1, seldom/not at all; 2, once a month; 3, once a week; 4, almost every day. Thus, the higher the score, the more frequent the symptom. Women prospectively recorded their hot flashes in daily diaries for 2 weeks, and the following scale was used to rate severity: mild (a slight sensation of heat that does not disturb daily life), moderate (intense sensation of heat while awake, accompanied by some perspiration), and severe (intense sensation of heat with profuse sweating that clearly interferes with daily life or sleep). Based on these diaries, a hot flash weekly weighted score (HFWWS)5 was calculated. We classified women reporting seven or more moderate to severe hot flashes per day (n = 72) as women with hot flashes. Women reporting only three or fewer mild hot flashes per day that did not interfere subjectively with daily activity (n = 78) or women reporting no hot flashes at all (n = 23) were classified as women without hot flashes (Fig. 1). Assessment of HRQL, general health, and sexual well-being All women were interviewed for lifestyle factors such as diet, education, employment, and physical exercise at baseline. The Women’s Health Questionnaire (WHQ) was used to measure HRQL, psychological well-being, and emotional wellbeing. This questionnaire, which has been validated in the Finnish language, is a reliable and well-documented instrument for clinical trials.13,14 It consists of 36 items capturing nine factors/domains of women’s health: vasomotor symptoms (2 items), somatic symptoms (7 items), anxiety and fears Menopause, Vol. 21, No. 7, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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SAVOLAINEN-PELTONEN ET AL TABLE 1. Baseline characteristics
Age, mean (SD), y Body mass index, mean (SD), kg/m2 Hot flash weekly weighted score, mean (SD) Serum follicle-stimulating hormone, mean (SD), IU/L Serum estradiol, mean (SD), pmol/L Age at menarche, mean (SD), y Age at menopause, mean (SD), y History of hormonal contraception, % Deliveries, mean (SD) Weekly use of alcohol, % Employed, % Absence from work (last 6 mo), % In a relationship, % Sleep disturbances, % Significant P values are bold.
Women with hot flashes (n = 72)
Women without hot flashes (n = 78)
P
52.2 (2.2) 22.8 (2.4) 161.2 (65.5) 67.7 (23.0) 80.8 (86.5) 13.2 (1.5) 50.5 (3.3) 71.8 1.9 (0.1) 60.0 94.4 33.8 68.6 73.2
52.6 (2.0) 23.1 (2.2) 7.0 (8.4) 78.2 (29.1) 58.7 (60.2) 13.2 (1.5) 50.9 (2.6) 66.7 1.8 (0.1) 60.3 96.2 35.4 74.4 34.2
0.246 0.454 G0.001 0.040 0.142 0.741 0.600 0.496 0.887 0.975 0.496 0.838 0.436 0.0001
(4 items), depression (7 items), sleep problems (3 items), sexual behavior (3 items), memory and concentration (3 items), menstrual cycleYrelated symptoms (such as abdominal bloating or breast tenderness; 4 items), and attractiveness (3 items). Each item was answered on a four-point scale (1-4) and reduced to a binary scale (1 and 2 = 0; 3 and 4 = 1) for scoring. A mean score for each item was calculated. The higher is the score, the better is the quality of life. The women themselves assessed general health using a visual analogue scale (VAS) ranging from 0 to 100, with higher scores indicating better health. Women also compared their current health state with their health state in the past 12 months (1, worse; 2, about the same; 3, better). Sexual well-being was assessed with the McCoy Female Sexuality Questionnaire,15 as modified by Nathorst-Boos et al.16 This implies a 10-item sex scale that provides an overall score and three subscales that denote sexual problems (two items), sexual satisfaction (five items), and satisfaction with partner (three items). Items consist of seven-point Likert scales (1, never; 7, always). A higher score reflects better sexual satisfaction, except for the sexual problems subscale. HT trial After baseline assessment, women were treated with a doubleblind, double-dummy techniqueVwith either transdermal estradiol hemihydrate gel 1 mg/day (TE), oral estradiol valerate 2 mg/day (OE), oral estradiol with medroxyprogesterone acetate 5 mg/day (OE + MPA), or placeboVfor 6 months. Estradiolbased regimens are most popular in Europe and the only ones available in Finland. The women completed the questionnaires before the commencement of HT and at 3 and 6 months of HT or placebo treatment. In addition, serum samples were collected for the assessment of estradiol and follicle-stimulating hormone (FSH) levels with routine laboratory methods before the trial and at 6 months. Statistical analysis Data were analyzed according to intention-to-treat principle (ie, all women were included in the analyses whether or not they completed the study). Missing data were imputed by
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SPSS linear interpolation method. Normality was assessed with the Shapiro-Wilk test. For normally distributed data, Student’s t test was used. For nonYnormally distributed data, Mann-Whitney U test or Wilcoxon signed ranks test was used. Frequencies were compared using Pearson’s W2 test, and correlations were determined using Pearson’s nonparametric correlation. P G 0.05 was considered statistically significant. All data are presented as mean (SD), unless specified otherwise. Analyses were carried out with SPSS software for Windows version 19.0 (SPSS Inc, Chicago, IL).
RESULTS The two study groups were comparable in primary clinical characteristics, except for hot flashes (Table 1). FSH levels were slightly higher in women without hot flashes than in those with hot flashes (P = 0.040). At baseline, insomnia/sleep disturbances, irritability, exhaustion, depressive mood, joint pains, palpitation, nausea, and edema were significantly more common in women with hot flashes (Tables 1, 2). Absence from work, however, was equally common in these groups. Women with hot flashes had significantly lower scores for all nine domains of the WHQ (Table 3). Furthermore, hot flashes, expressed as HFWWS, associated significantly with poor sleep (correlation coefficient r = j0.525, P G 0.0001), somatic symptoms (r = j0.348, P G 0.0001), menstrual cycleYresembling complaints (r = j0.304, P G 0.0001), anxiety and fears (r = j0.283, P G 0.0001), poor memory and concentration (r = j0.279, P = 0.001), and sexual behavior (r = j0.174, P = 0.035), but no association emerged between HFWWS and depression or attractiveness. Hot flashes were also associated with a decrease in general health, as seen on the VAS (r = j0.227, P = 0.005). Of the 150 women who started an HT trial regimen, 7 women withdrew their consent, and 2 women who were using true HT discontinued the trial because of spotting at 3 months. In addition, data were not complete in nine women (Fig. 1). The data were analyzed according to intention-to-treat principle, as described in BMethods[; thus, all available data were analyzed. * 2013 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
IMPACT OF HOT FLASHES ON QUALITY OF LIFE TABLE 2. Prevalence of menopause-related symptoms at baseline in women with or without hot flashes, and their correlation with HFWWS Women with hot flashes
Women without hot flashes
Insomnia 2.5 (1.1) 1.6 (0.8) Feeling exhausted 2.5 (0.7) 1.9 (0.7) Irritability, nervousness 2.4 (0.9) 1.7 (0.7) Depressive mood 1.7 (0.9) 1.1 (0.3) Palpitation 1.7 (0.8) 1.2 (0.5) Edema 1.6 (0.8) 1.2 (0.5) Numbness 1.5 (0.7) 1.3 (0.6) Nausea 1.2 (0.5) 1.0 (0.2) Aching joints or muscles 2.5 (1.0) 2.0 (1.0) Fatigue 1.4 (0.7) 1.2 (0.4) Headache 1.8 (0.8) 1.5 (0.6) Vaginal or genital dryness 1.7 (0.9) 1.3 (0.6) Dryness of mouth 1.4 (0.7) 1.3 (0.7) Dizziness 1.2 (0.5) 1.2 (0.5) Shortness of breath 1.1 (0.3) 1.0 (0.3) A lump feeling in the throat 1.2 (0.5) 1.2 (0.5) Trembling 1.1 (0.5) 1.2 (0.5) Data are presented as mean (SD). Significant P values are bold. 1, Seldom/not at all; 2, once a month; 3, once a week; 4, almost every day. HFWWS, hot flash weekly weighted score.
All HT regimens were accompanied by comparable estradiol levels at 6 months (TE, 204 [177] pmol/L; OE, 218 [104] pmol/L; OE + MPA, 174 [86] pmol/L), which were significantly higher (P G 0.0001) than those in the placebo group (69 [103] pmol/L). Furthermore, FSH levels decreased in the HT groups (data not shown). Although oral estradiol alone or with MPA tended to alleviate hot flashes slightly more effectively than did TE, the difference was not significant; therefore, women with different HT regimens were combined together and considered as one single HT group. In women with hot flashes, 6 months of HT showed a significant benefit over placebo in vasomotor symptoms (P G 0.0001), sleep (P = 0.003), anxiety and fears (P = 0.005), and memory and concentration (P G 0.0001; Fig. 2). Placebo use also showed a tendency toward improvement of WHQ scores at 3 months (Fig. 2). At 6 months, HT use significantly relieved exhaustion, irritability, edema, joint and muscle pains, and vaginal dryness in women with hot flashes at baseline (Table 4). HT improved general health in women with hot flashes (2.0 [0.3] vs 1.8 [0.5], HT vs placebo, P = 0.040), but not in women without flashes. HT did not induce statistically significant changes in VAS in either group. Finally, HT did not affect sexual well-being (sexual satisfaction, sexual problems,
P
Correlation with HFWWS (r)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.001 0.003 0.005 0.288 0.108 0.068 0.743 0.648 0.104 0.771 0.886
0.441 0.379 0.250 0.235 0.319 0.215 0.242 0.208 0.197 0.081 0.124 0.072 0.063 0.033 0.099 j0.042 0.060
P G0.0001 G0.0001 0.002 0.004 G0.0001 0.008 0.003 0.010 0.016 0.332 0.139 0.382 0.450 0.686 0.230 0.617 0.466
or satisfaction with partner; 80.6% of women had a sexual partner) in women with or without flashes (Table 5). DISCUSSION With an increasing number of postmenopausal women and with increasing life expectancy, quality of life in these women has become the focus of intense research.17 Reliable assessment of HRQL is, however, challenging18 because menopausal symptoms show large individual variations. Therefore, we used multiple validated research tools specifically designed for postmenopausal women to objectively measure HRQL in recently postmenopausal women. These tests have previously been used in studies of Scandinavian postmenopausal populations19,20 or other populations.21,22 A general consensus is that HRQL decreases soon after the onset of menopause.17,23 This is primarily attributed to hot flashes, which are rather specific consequences of reduced estrogen levels.24 In our research setting, we analyzed the impact of hot flashes, which were recorded prospectively and quantified as objective scores,5 on different life quality variables. We can confirm that hot flashes are the major determinants of a decrease in HRQL in recently postmenopausal women. However, their contribution to the different variables
TABLE 3. Scores for health-related quality of life at baseline, as measured with the Women’s Health Questionnaire, in women with or without hot flashes Women with hot flashes Vasomotor symptoms 0.059 (0.201) Anxiety and fears 0.851 (0.193) Sleep 0.562 (0.296) Somatic symptoms 0.665 (0.225) Menstrual symptoms 0.752 (0.247) Memory and concentration 0.623 (0.291) Depression 0.854 (0.152) Sexual 0.593 (0.296) Attractiveness 0.687 (0.364) Data are presented as mean (SD). Significant P values are bold.
Women without hot flashes
P
0.856 (0.258) 0.951 (0.105) 0.874 (0.221) 0.827 (0.151) 0.912 (0.162) 0.814 (0.248) 0.919 (0.116) 0.753 (0.226) 0.827 (0.327)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.001 0.001 0.026
Menopause, Vol. 21, No. 7, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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SAVOLAINEN-PELTONEN ET AL
FIG. 2. Changes in the different dimensions of the Women’s Health Questionnaire in women with or without hot flashes at 3 and 6 months after hormone therapy (HT) or placebo. Data are presented as mean (SEM). P G 0.05 was considered statistically significant.
reflecting HRQL varied from one symptom to another. The domains most strongly associated with hot flashes at baseline were poor sleep, somatic symptoms, anxiety and fears, poor memory and concentration, sexual function, and menstrual cycleYresembling symptoms. These results were partly expected in the light of previous data.4,25,26 Memory, however, seems to be an exception because hot flashes have deteriorated
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memory in some27
Health-related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy Hanna Savolainen-Peltonen, MD, PhD,1,2 Hanna Hautama¨ki, MD,1 Pauliina Tuomikoski, MD, PhD,1 Olavi Ylikorkala, MD, PhD,1 and Tomi S. Mikkola, MD, PhD1,2 Abstract Objective: We assessed the impact of hot flashes and various forms of hormone therapy on health-related quality of life and sexual well-being in recently postmenopausal women. Methods: We prospectively interviewed 150 healthy women about hot flashes and health-related quality of life (using the Women’s Health Questionnaire and the McCoy Female Sexuality Questionnaire), menopauserelated symptoms, and general health. 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. Results: At baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = j0.525, P G 0.0001), somatic symptoms such as muscle pains (r = j0.348, P G 0.0001), menstrual cycleYresembling complaints (r = j0.304, P G 0.0001), anxiety and fears (r = j0.283, P G 0.0001), decreased memory and concentration (r = j0.279, P = 0.001), and sexual behavior (r = j0.174, P = 0.035). The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group for further analysis. In women with baseline flashes, hormone therapy use significantly improved the scores for sleep (0.787 [0.243] vs 0.557 [0.249], hormone therapy vs placebo, P = 0.001, at 6 mo), memory and concentration capacity (0.849 [0.228] vs 0.454 [0.301], P G 0.0001, at 6 mo), and anxiety and fears (0.942 [0.133] vs 0.826 [0.193], P = 0.005, at 6 mo). Hormone therapy use showed no significant impact on these variables in women without baseline flashes. Conclusions: Hot flashes contribute differently to various variables affecting health-related quality of life shortly after menopause. Estradiol or an estradiolYmedroxyprogesterone acetate combination similarly alleviates hot flashes and improves health-related quality of life in relation to elimination of hot flashes. Hormone therapy use does not confer any detectable quality-of-life benefit over placebo in women without disturbing baseline flashes. Key Words: Menopause Y Hot flashes Y Quality of life Y Hormone therapy.
F
ifty percent to 80% of women complain about menopausal symptoms such as hot flashes, night sweats, sleep disturbances, tiredness, and depressive mood. They are the principal determinants of a reduced health-related quality of life (HRQL), which is detectable quite soon after the onset of menopause.1 It is a common belief that hot flashes (originating from hypothalamic dysregulation of thermal centers as a consequence of reduced estrogen levels) would be the primary sign of menopause, and that other mental or somatic
Received July 7, 2013; revised and accepted September 5, 2013. From the 1Department of Obstetrics and Gynecology, Helsinki University Central Hospital and the University of Helsinki, Helsinki, Finland; and 2Folkha¨lsan Research Institute, Helsinki, Finland. Funding/support: This study was supported by a Helsinki University Central Hospital research grant, the Finnish Medical Foundation, the Foundation of Paulo, the Finnish Menopause Society, and the Jalmari and Rauha Ahokas Foundation. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Tomi S. Mikkola, MD, PhD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, PO Box 140, Helsinki FIN-00029 HUS, Finland. E-mail: [email protected]
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symptoms would only be secondary phenomena to hot flashes. However, in view of the profound effects of estrogen on, for example, neural cells and connective tissues, the secondary characters of many nonflash symptoms can be questioned.2,3 The delineation between flashes and nonflash symptoms in clinical research is difficult. First, severe hot flashes, with or without night sweats, are often so dominant that they override the other symptoms. Second, women show marked differences in their capacity to tolerate hot flashes; some are disturbed by flashes that are readily acceptable by others.4 A woman may not be totally unbiased while judging her hot flashes; undue negative coverage of hormone therapy (HT) by the media has influenced some women to BtolerateB even rather severe symptoms to avoid the initiation of HT. Third, hot flashes show marked day-to-day or even hour-to-hour variations; therefore, their reliable assessment is prone to large interindividual and intraindividual fluctuations. Preferably, hot flashes should be assessed prospectively with interview tools, which aim to be maximally objective5,6; this was not the case in many previous quality-of-life trials.7,8 Generally, only women with intolerable hot flashes are considered as candidates for HT.
Menopause, Vol. 21, No. 7, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
IMPACT OF HOT FLASHES ON QUALITY OF LIFE
FIG. 1. Flow chart of the study showing the impact of hot flashes on health-related quality of life.
Oral or transdermal estrogen is a drug of choice for hot flashes and other menopausal symptoms. Estrogen-only therapy is applicable for hysterectomized women, whereas nonhysterectomized women must combine estrogen with a progestin for endometrial protection. Progestin may, however, oppose or even eliminate the positive effects of estrogen.9,10 In this regard, medroxyprogesterone acetate (MPA), which was combined with conjugated equine estrogens in the Women’s Health Initiative trial,8 has been most discussed because MPA may worsen cognitive function.11 The effect of different hormonal regimens on HRQL is poorly understood. We analyzed the impact of hot flashes on HRQL, general health, and sexual well-being within the first 6 to 36 months after menopause. The women were classified into those with or without hot flashes and treated with transdermal or oral HT, with or without MPA, in a randomized placebo-controlled trial for 6 months to see how the treatments affect life quality variables in these women. METHODS Study population A total of 150 postmenopausal women (mean [SD] age, 53.2 [0.2] y; mean [SD] time since menopause, 19.5 [0.8] mo) were included in the trial, as reported previously.12 The women received oral and written information about the study, and they all agreed to take part in the forthcoming HT trial regardless of their symptoms. This study was approved by the Helsinki University Women’s Hospital ethics committee and registered with the National Agency for Medicine (EudraCT 2004-005091-16) and the US National Institutes of Health Clinical Registry (NCT00668603). The study was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki.
Menopausal symptoms Women were interviewed with a structured questionnaire for 19 leading menopausal symptoms (eg, insomnia, depressive mood, nervousness, aching joints or muscles, or vaginal dryness) occurring in the past 2 weeks. The incidence of the symptoms was scored as follows: 1, seldom/not at all; 2, once a month; 3, once a week; 4, almost every day. Thus, the higher the score, the more frequent the symptom. Women prospectively recorded their hot flashes in daily diaries for 2 weeks, and the following scale was used to rate severity: mild (a slight sensation of heat that does not disturb daily life), moderate (intense sensation of heat while awake, accompanied by some perspiration), and severe (intense sensation of heat with profuse sweating that clearly interferes with daily life or sleep). Based on these diaries, a hot flash weekly weighted score (HFWWS)5 was calculated. We classified women reporting seven or more moderate to severe hot flashes per day (n = 72) as women with hot flashes. Women reporting only three or fewer mild hot flashes per day that did not interfere subjectively with daily activity (n = 78) or women reporting no hot flashes at all (n = 23) were classified as women without hot flashes (Fig. 1). Assessment of HRQL, general health, and sexual well-being All women were interviewed for lifestyle factors such as diet, education, employment, and physical exercise at baseline. The Women’s Health Questionnaire (WHQ) was used to measure HRQL, psychological well-being, and emotional wellbeing. This questionnaire, which has been validated in the Finnish language, is a reliable and well-documented instrument for clinical trials.13,14 It consists of 36 items capturing nine factors/domains of women’s health: vasomotor symptoms (2 items), somatic symptoms (7 items), anxiety and fears Menopause, Vol. 21, No. 7, 2014
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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SAVOLAINEN-PELTONEN ET AL TABLE 1. Baseline characteristics
Age, mean (SD), y Body mass index, mean (SD), kg/m2 Hot flash weekly weighted score, mean (SD) Serum follicle-stimulating hormone, mean (SD), IU/L Serum estradiol, mean (SD), pmol/L Age at menarche, mean (SD), y Age at menopause, mean (SD), y History of hormonal contraception, % Deliveries, mean (SD) Weekly use of alcohol, % Employed, % Absence from work (last 6 mo), % In a relationship, % Sleep disturbances, % Significant P values are bold.
Women with hot flashes (n = 72)
Women without hot flashes (n = 78)
P
52.2 (2.2) 22.8 (2.4) 161.2 (65.5) 67.7 (23.0) 80.8 (86.5) 13.2 (1.5) 50.5 (3.3) 71.8 1.9 (0.1) 60.0 94.4 33.8 68.6 73.2
52.6 (2.0) 23.1 (2.2) 7.0 (8.4) 78.2 (29.1) 58.7 (60.2) 13.2 (1.5) 50.9 (2.6) 66.7 1.8 (0.1) 60.3 96.2 35.4 74.4 34.2
0.246 0.454 G0.001 0.040 0.142 0.741 0.600 0.496 0.887 0.975 0.496 0.838 0.436 0.0001
(4 items), depression (7 items), sleep problems (3 items), sexual behavior (3 items), memory and concentration (3 items), menstrual cycleYrelated symptoms (such as abdominal bloating or breast tenderness; 4 items), and attractiveness (3 items). Each item was answered on a four-point scale (1-4) and reduced to a binary scale (1 and 2 = 0; 3 and 4 = 1) for scoring. A mean score for each item was calculated. The higher is the score, the better is the quality of life. The women themselves assessed general health using a visual analogue scale (VAS) ranging from 0 to 100, with higher scores indicating better health. Women also compared their current health state with their health state in the past 12 months (1, worse; 2, about the same; 3, better). Sexual well-being was assessed with the McCoy Female Sexuality Questionnaire,15 as modified by Nathorst-Boos et al.16 This implies a 10-item sex scale that provides an overall score and three subscales that denote sexual problems (two items), sexual satisfaction (five items), and satisfaction with partner (three items). Items consist of seven-point Likert scales (1, never; 7, always). A higher score reflects better sexual satisfaction, except for the sexual problems subscale. HT trial After baseline assessment, women were treated with a doubleblind, double-dummy techniqueVwith either transdermal estradiol hemihydrate gel 1 mg/day (TE), oral estradiol valerate 2 mg/day (OE), oral estradiol with medroxyprogesterone acetate 5 mg/day (OE + MPA), or placeboVfor 6 months. Estradiolbased regimens are most popular in Europe and the only ones available in Finland. The women completed the questionnaires before the commencement of HT and at 3 and 6 months of HT or placebo treatment. In addition, serum samples were collected for the assessment of estradiol and follicle-stimulating hormone (FSH) levels with routine laboratory methods before the trial and at 6 months. Statistical analysis Data were analyzed according to intention-to-treat principle (ie, all women were included in the analyses whether or not they completed the study). Missing data were imputed by
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SPSS linear interpolation method. Normality was assessed with the Shapiro-Wilk test. For normally distributed data, Student’s t test was used. For nonYnormally distributed data, Mann-Whitney U test or Wilcoxon signed ranks test was used. Frequencies were compared using Pearson’s W2 test, and correlations were determined using Pearson’s nonparametric correlation. P G 0.05 was considered statistically significant. All data are presented as mean (SD), unless specified otherwise. Analyses were carried out with SPSS software for Windows version 19.0 (SPSS Inc, Chicago, IL).
RESULTS The two study groups were comparable in primary clinical characteristics, except for hot flashes (Table 1). FSH levels were slightly higher in women without hot flashes than in those with hot flashes (P = 0.040). At baseline, insomnia/sleep disturbances, irritability, exhaustion, depressive mood, joint pains, palpitation, nausea, and edema were significantly more common in women with hot flashes (Tables 1, 2). Absence from work, however, was equally common in these groups. Women with hot flashes had significantly lower scores for all nine domains of the WHQ (Table 3). Furthermore, hot flashes, expressed as HFWWS, associated significantly with poor sleep (correlation coefficient r = j0.525, P G 0.0001), somatic symptoms (r = j0.348, P G 0.0001), menstrual cycleYresembling complaints (r = j0.304, P G 0.0001), anxiety and fears (r = j0.283, P G 0.0001), poor memory and concentration (r = j0.279, P = 0.001), and sexual behavior (r = j0.174, P = 0.035), but no association emerged between HFWWS and depression or attractiveness. Hot flashes were also associated with a decrease in general health, as seen on the VAS (r = j0.227, P = 0.005). Of the 150 women who started an HT trial regimen, 7 women withdrew their consent, and 2 women who were using true HT discontinued the trial because of spotting at 3 months. In addition, data were not complete in nine women (Fig. 1). The data were analyzed according to intention-to-treat principle, as described in BMethods[; thus, all available data were analyzed. * 2013 The North American Menopause Society
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
IMPACT OF HOT FLASHES ON QUALITY OF LIFE TABLE 2. Prevalence of menopause-related symptoms at baseline in women with or without hot flashes, and their correlation with HFWWS Women with hot flashes
Women without hot flashes
Insomnia 2.5 (1.1) 1.6 (0.8) Feeling exhausted 2.5 (0.7) 1.9 (0.7) Irritability, nervousness 2.4 (0.9) 1.7 (0.7) Depressive mood 1.7 (0.9) 1.1 (0.3) Palpitation 1.7 (0.8) 1.2 (0.5) Edema 1.6 (0.8) 1.2 (0.5) Numbness 1.5 (0.7) 1.3 (0.6) Nausea 1.2 (0.5) 1.0 (0.2) Aching joints or muscles 2.5 (1.0) 2.0 (1.0) Fatigue 1.4 (0.7) 1.2 (0.4) Headache 1.8 (0.8) 1.5 (0.6) Vaginal or genital dryness 1.7 (0.9) 1.3 (0.6) Dryness of mouth 1.4 (0.7) 1.3 (0.7) Dizziness 1.2 (0.5) 1.2 (0.5) Shortness of breath 1.1 (0.3) 1.0 (0.3) A lump feeling in the throat 1.2 (0.5) 1.2 (0.5) Trembling 1.1 (0.5) 1.2 (0.5) Data are presented as mean (SD). Significant P values are bold. 1, Seldom/not at all; 2, once a month; 3, once a week; 4, almost every day. HFWWS, hot flash weekly weighted score.
All HT regimens were accompanied by comparable estradiol levels at 6 months (TE, 204 [177] pmol/L; OE, 218 [104] pmol/L; OE + MPA, 174 [86] pmol/L), which were significantly higher (P G 0.0001) than those in the placebo group (69 [103] pmol/L). Furthermore, FSH levels decreased in the HT groups (data not shown). Although oral estradiol alone or with MPA tended to alleviate hot flashes slightly more effectively than did TE, the difference was not significant; therefore, women with different HT regimens were combined together and considered as one single HT group. In women with hot flashes, 6 months of HT showed a significant benefit over placebo in vasomotor symptoms (P G 0.0001), sleep (P = 0.003), anxiety and fears (P = 0.005), and memory and concentration (P G 0.0001; Fig. 2). Placebo use also showed a tendency toward improvement of WHQ scores at 3 months (Fig. 2). At 6 months, HT use significantly relieved exhaustion, irritability, edema, joint and muscle pains, and vaginal dryness in women with hot flashes at baseline (Table 4). HT improved general health in women with hot flashes (2.0 [0.3] vs 1.8 [0.5], HT vs placebo, P = 0.040), but not in women without flashes. HT did not induce statistically significant changes in VAS in either group. Finally, HT did not affect sexual well-being (sexual satisfaction, sexual problems,
P
Correlation with HFWWS (r)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.001 0.003 0.005 0.288 0.108 0.068 0.743 0.648 0.104 0.771 0.886
0.441 0.379 0.250 0.235 0.319 0.215 0.242 0.208 0.197 0.081 0.124 0.072 0.063 0.033 0.099 j0.042 0.060
P G0.0001 G0.0001 0.002 0.004 G0.0001 0.008 0.003 0.010 0.016 0.332 0.139 0.382 0.450 0.686 0.230 0.617 0.466
or satisfaction with partner; 80.6% of women had a sexual partner) in women with or without flashes (Table 5). DISCUSSION With an increasing number of postmenopausal women and with increasing life expectancy, quality of life in these women has become the focus of intense research.17 Reliable assessment of HRQL is, however, challenging18 because menopausal symptoms show large individual variations. Therefore, we used multiple validated research tools specifically designed for postmenopausal women to objectively measure HRQL in recently postmenopausal women. These tests have previously been used in studies of Scandinavian postmenopausal populations19,20 or other populations.21,22 A general consensus is that HRQL decreases soon after the onset of menopause.17,23 This is primarily attributed to hot flashes, which are rather specific consequences of reduced estrogen levels.24 In our research setting, we analyzed the impact of hot flashes, which were recorded prospectively and quantified as objective scores,5 on different life quality variables. We can confirm that hot flashes are the major determinants of a decrease in HRQL in recently postmenopausal women. However, their contribution to the different variables
TABLE 3. Scores for health-related quality of life at baseline, as measured with the Women’s Health Questionnaire, in women with or without hot flashes Women with hot flashes Vasomotor symptoms 0.059 (0.201) Anxiety and fears 0.851 (0.193) Sleep 0.562 (0.296) Somatic symptoms 0.665 (0.225) Menstrual symptoms 0.752 (0.247) Memory and concentration 0.623 (0.291) Depression 0.854 (0.152) Sexual 0.593 (0.296) Attractiveness 0.687 (0.364) Data are presented as mean (SD). Significant P values are bold.
Women without hot flashes
P
0.856 (0.258) 0.951 (0.105) 0.874 (0.221) 0.827 (0.151) 0.912 (0.162) 0.814 (0.248) 0.919 (0.116) 0.753 (0.226) 0.827 (0.327)
G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 G0.0001 0.001 0.001 0.026
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FIG. 2. Changes in the different dimensions of the Women’s Health Questionnaire in women with or without hot flashes at 3 and 6 months after hormone therapy (HT) or placebo. Data are presented as mean (SEM). P G 0.05 was considered statistically significant.
reflecting HRQL varied from one symptom to another. The domains most strongly associated with hot flashes at baseline were poor sleep, somatic symptoms, anxiety and fears, poor memory and concentration, sexual function, and menstrual cycleYresembling symptoms. These results were partly expected in the light of previous data.4,25,26 Memory, however, seems to be an exception because hot flashes have deteriorated
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memory in some27
