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Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women
Maturitas 44 (2003) 157 /163 www.elsevier.com/locate/maturitas
Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women Marco Gambacciani *, Massimo Ciaponi, Barbara Cappagli, Patrizia Monteleone, Caterina Benussi, Gemma Bevilacqua, Andrea R. Genazzani Department of Obstetrics and Gynecology, University of Pisa, Via Roma 67, 56100 Pisa, Italy Received 20 February 2002; received in revised form 19 September 2002; accepted 24 October 2002
Abstract Objectives: To describe the effects of low dose hormonal replacement therapy (LD-HRT) on quality of life in early postmenopausal women, since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms, which may greatly affect quality of life. Methods: Fifty normal postmenopausal women were recruited and randomly treated with LD-HRT, 17b-estradiol (1 mg/day) and norethisterone acetate (0.5 mg/day) (LDHRT) or calcium supplement (controls). No significant differences in age, age at menopause, the presence of chronic diseases and socio-economic status were present in the two groups. The Women’s Health Questionnaire (WHQ), a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and after 6 and 12 weeks of treatment in both groups. Results: At baseline no significant differences in WHQ scores were present in the two groups. In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation. Conversely, the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms, somatic symptoms, anxiety/fear, depressed mood and sleep problem items. No effects on memory/concentration and menstrual symptoms areas were evident. Conclusion: Although quality of life is also and may be mainly influenced by socio-economic and cultural factors, LD-HRT definitively can improve not only vasomotor symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estradiol; Noretisterone acetate; Hormonal replacement therapy; Quality of life
1. Introduction * Corresponding author. Tel.: /39-50-992385; fax: /39-50553410 E-mail address: [email protected] (M. Gambacciani).
Nowadays, quality of life (QoL) is an important outcome that reflect the way patients feel and function. The menopause transition in mid age
0378-5122/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 3 2 7 - 4
158
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
women often brings along mood alterations, sleeplessness, hot flushes and sweats, sexual dysfunction, the impact of which may be noteworthy on the QoL. Thus, QoL evaluation can be considered an essential component to provide a comprehensive picture of the effect of the menopause and to assess the possible benefits of different treatments. To this end, different scales have been used to evaluate QoL in postmenopause [1 /8]. Recently the Italian version of the Women’s Health Questionnaire (WHQ) has been validated in an Italian population of menopausal women, with results sustaining the use of WHQ to investigate QoL in Italian postmenopausal women population [5]. In this study the item /scale correlations, used to evaluate item-internal consistency, exceeded the minimum accepted value of 0.30 for all items with the exception of three, two relative to depression (item 10, r /0.15 and item 07, r / 0.22) and one to somatic symptoms (item 23, r / 0.24). The item-discriminant validity was measured by the scaling success rate, that is the percentage of times items correlated significantly higher with its corrected scale score than with other scale scores in the instrument. The scaling success rate was high for all the scales, ranging between 83 and 100%. In particular, for vasomotor symptoms, sexual behavior and menstrual symptoms the correlation between an item and its hypothesized scale always exceeded correlations with all other scales [5]. Also the reliability of scale scores was exellent. For seven out of nine scales the Chronbach alpha coefficient was in the range of 0.6 /0.7 (for group comparisons, a minimum value of 0.5 [9,10] to 0.7 [11] is generally recommended). For two scales, i.e. menstrual symptoms and attractiveness, the internal-consistency reliability indexes were less satisfactory. Chronbach alpha coefficient for the summary scale, composed of 35 items, was 0.88. Test /retest reliability was excellent, with coefficients largely exceeding the value of 0.70 for all the scales [5]. The perception of QoL is significantly modified during the peri/ postmenopausal period [9 /11]. Hormone replacement therapy (HRT) can be used to reverse or improve climacteric symptoms, and to maintain the physical and psychological day-to-day functioning of the postmenopausal woman [12 /16].
However, until now, scarce information is available on the possible effects of low dose hormonal replacement therapy (LD-HRT) on QoL [17]. The aim of this longitudinal study was to describe the effects of LD-HRT on QoL in a group of early postmenopausal women and compare their outcome in term of QoL with untreated similar postmenopausal women group.
2. Materials and methods Ethical Committee of our Department approved the study protocol. Fifty postmenopausal women were recruited and assigned to LD-HRT or calcium /vitamin treated group (control group), using a randomisation list (yes /no). The LD-HRT group received a daily pill containing 1 mg estradiol/0.5 mg noretisterone acetate each pill (ActivelleTM, Novo Nordisk) for 28 days on 28. The control group receiving a daily supplement of calcium (1000 mg/day). QoL was evaluated by a questionnaire (the WHQ) handed to the women during a visit to the centre. The WHQ was developed in England to investigate psychological and somatic symptoms experienced by peri and postmenopausal women [1,4 /6], and its psychometric properties have already been well documented [1,4 /6]. The questionnaire is composed of 36 questions rated on four-point scales, indicating the extent to which symptoms or sensations are experienced. The higher the score, the more pronounced is the distress and dysfunction. The 36 items are combined into nine subscales describing somatic symptoms (seven items), depressed mood (seven items), memory/concentration difficulties (three items), anxiety/fears (four items), sexual behavior (three items), vasomotor symptoms (two items), sleep problems (three items), menstrual symptoms (four items) and attractiveness (two items). The cultural adaptation of the WHQ into Italian has been performed by the Mapi Research Institute, Lyon, France. The forward/backward method was employed to ensure conceptual equivalence. Briefly, a QoL specialist was recruited as project manager and WHQ was translated from English to Italian by two independent professional transla-
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
tors, native Italian language speakers and bilingual in the source language. The two versions were reviewed with the translators and the project manager and an agreement was reached for a pre-final Italian version of the questionnaire. A backward translation (from Italian to English) was performed by a professional translator, English native speaker and bilingual in the target language. The agreed final English translation was thus evaluated by the originator of the WHQ (M. Hunter) who gave her approval to the use of the Italian version of the questionnaire. The WHQ was already validated in a large Italian population of pre, peri and postmenopausal women and was shown to be a valid, reliable and reproducible instrument [5]. The questionnaire was anonymous, filled in at home and then returned at each visit to the centre. For each enrolled woman, the gynaecologist collected socio-demographic and clinical data on ad hoc forms. Each questionnaire was matched with the clinical data by a code present on both forms. No significant differences in age, years since menopause (YSM), body mass index (BMI), Follicle-stimulating-hormone (FSH), Estradiol plasma levels and socioeconomic level were found between the two groups (Tables 1 and 2). Moreover, the two groups of women were free from chronic diseases (cancer, cardiovascular disease, depression treated with drugs and other serious concomitan pathologies) and socio-economic problems (Table 2) known to affect QoL. All the 50 women recruited in the study filled in the questionnaire (25 of the LD-HRT group and 25 of Table 1 Control group, postmenopausal women receiving 1000 mg of calcium per day (n /25); LD-HRT, postmenopausal women receiving oral pill contain 1 mg estradiol/0.5 mg noretisterone acetate per day (n /25)
Age (year) YSM BMI (kg/m2) FSH (IU/l) Estradiol (pg/ml)
Control
LD-HRT
54.39/0.3 4.59/0.7 24.59/0.9 85.49/7.8 18.49/2.3
54.49/0.5 4.79/0.5 24.19/0.5 81.59/4.5 20.29/3.4
YSM, years since menopause; BMI, body mass index; FSH, follicle-stimulating hormone.
159
Table 2 General characteristics of women in control group, postmenopausal women receiving 1000 mg of calcium per day (n /25); and LD-HRT, postmenopausal women receiving oral pill contain 1 mg estradiol/0.5 mg noretisterone acetate per day (n /25) Control
LD-HRT
School education 0 /8 years 9 /13 years /13 years
11 (44%) 11 (44%) 3 (12%)
10 (40%) 10 (40%) 5 (20%)
Occupation Employed Retired Housewife Unemployed
10 (40%) 5 (20%) 10 (40%) 0 (0%)
11 (44%) 5 (20%) 9 (36%) 0 (0%)
Marital status Single Married Widowed/divorced
1 (4%) 24 (96%) 0 (0%)
2 (8%) 23 (92%) 0 (0%)
Social class Middle class Working class
10 (40%) 15 (60%)
10 (40%) 15 (60%)
untreated group; response rate 100%). The questionnaire was performed at baseline, after 6 and 12 week of study. QoL was investigated by using a questionnaire specifically designed to evaluate the impact of menopausal symptoms. All the results are reported as the Mean9/S.E. of absolute values. Baseline values were compared by Student’s t -test. Two way analysis of variance for repeated measures and factorial analysis of variance were used to test the differences within and between the groups, respectively. The post-hoc comparison was made by Scheffe F -test.
3. Results No significant differences in age, YSM, BMI, FSH and Estradiol plasma levels were present in the two groups (Table 1). Basal scores in the different nine subscales were similar in the two groups (Figs. 1 /3). In the LD-HRT treated group a significant (P B/0.05) decrease from baseline values in the scores of six out of nine of the WHQ domains was evident after 6 and 12 weeks of
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Fig. 1. Depressed mood, Somatic symptoms and memory/concentration items (mean9/S.E.) at baseline (0 weeks), 6, and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
treatment (Figs. 1 /3). The scores improvement included vasomotor symptoms, sexual behaviour, depressed mood, somatic symptoms, anxiety/fear and sleep problem items (Figs. 1/3). In addition, all of the items mentioned above showed a significant difference (P B/0.05) between LDHRT and control group after 12 weeks of study. A particular feature is shown by vasomotor symptoms item that presented a significant (P B/ 0.05) difference between LD-HRT and control group till from the sixth week of observation (Fig. 2). On the contrary, no statistically significant differences within the LD-HRT treated group and between this group and the control group were found for memory concentration, menstrual symptoms and attractiveness items (Figs. 1 and 3, respectively). Also the women of control group showed an improvement for some items (somatic symptoms, memory/concentration, vasomotor symptoms, anxiety/fear, sleep problem) (Figs. 1/
3). The improvement reaches the peak (but not the statistical significance) around the sixth week of treatment and than decline (Figs. 1/3). However, after 12 weeks of treatment, the changes in the control group were less pronounced that those observed in LD-HRT treated group and did not reach statistical significance (Figs. 1 /3).
4. Discussion This is the first longitudinal randomized trial showing the effects of low dose HRT on QoL in early menopausal women. Present data show that short term LD-HRT can improve QoL in symptomatic women. Wiklund et al. [18] in a noncomparative Swedish study also showed that the quality of life of menopausal women improved after treatment with Estraderm TTS to a level comparable to that of a nonmenopausal reference
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
161
Fig. 2. Vasomotor symptoms, anxiety/fear and sexual behaviour items (mean9/S.E.) at baseline (0 weeks), 6 and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
group. Ditkoff et al. [19] demonstrated the improvement of psychologic functions in asymptomatic women by means of estrogen unaccompanied by progestogen. Although the instruments used by Ditkoff et al. were not specific to the assessment of quality of life, the authors themselves suggested that their results indicate a beneficial effect of unopposed estrogen on quality of life. These studies confirm that the effect of estrogen on quality of life is not merely caused by its clinical efficacy on vasomotor symptoms, as shown by its effectiveness, regardless of the presence or absence of the flushes [19]. Perceptions of well-being in healthy, postmenopausal women depend not only on biological changes experienced as consequence of estrogen deprivation, but also on socio-economic circumstances, individual cultural and personal experiences [5]. In this way, the effects observed after such a short term observation can not be ascribed
to relevant variation in socioeconomic or cultural status of LD-HRT treated women. LD-HRT users showed a significantly better QoL almost in all the symptoms scores of the WHQ, with the only exceptions of menstrual symptoms, memory/concentration and attractivness. In particular, LD-HRT users showed a lower probability of reporting anxiety/fears (Fig. 2). When looking at menopause symptoms, LDHRT users showed highly significant better outcomes in those areas which are more directly attributable to hormonal changes of mid age, namely vasomotor symptoms and sexual problems (Fig. 2). The overall picture emerging from this analysis suggests that HRT can be of benefit for many of the postmenopausal mood changes, sexual problems and vasomotor symptoms (Figs. 1 and 2), while untreated women show no significant alteration in the incidence of the disturbs investigated by the nine items (Figs. 1 /3).
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Fig. 3. Sleep problems, menstrual symptoms and Attractiveness items (mean9/S.E.) at baseline (0 weeks), 6 and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
In future studies the assessment of QoL will be an essential tool along with clinical and laboratory evaluation, for estimating the efficacy of therapy. The great majority of the larger trials had some possible limitation depends on the cross-sectional nature of the design, which can only indicate whether associations exist, but does not allow determining the direction of causality. Indeed our study represents a small sample of postmenopausal women, but the longitudinal nature of the research makes it quite interesting. Our study shows that also LD-HRT has the potential of improving not only symptoms, but also more general aspects of physical and psychological well-being, minimizing the side effects correlated to hormone use, at least at the standard doses actually used. Further therapeutic strategies should take into account that at a time, when mid-aged women are both culturally aware of the negative aspects
related to the menopause and need to maintain a good level of social and physical functioning, patient-centered evaluation is more and more important, in order to be able to provide information on how the treatments proposed affect different aspects of QoL. The demonstration of efficacy of LD-HRT furnishes us an additive tool in the field of postmenopausal correlated syndrome treatment.
References [1] Hunter M. The Women’s Health Questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992;7:45 /54. [2] Hilditch JT, Lewis J, Peter A, van Maris B, Ross A, Frassen E, Guyatt GH, Norton PG, Dunn E. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 1996;24:161 /75.
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163 [3] Le Floch JP. Validation d’un questionnaire d’e´valuation de la qualite´ de vie en me´nopause. Reprod Hum Horm 1997;10:147 /57. [4] Hunter M. The Women’s Health Questionnaire (WHQ): the development, standardization and application of a measure of mid-aged women’s emotional and physical health. Quality Life Res 2000;9:733 /8. [5] Genazzani AR, Nicolucci A, Campagnoli C, et al. Validation of Italian version of the Women’s Health Questionnaire: assessment of quality of life of women from the general population and those attending menopause centers. Climacteric 2002;5(1):70 /7. [6] Wiklund I, Karlberg J, Lindgren R, Sandin K, Mattson LA. A Swedish version of the Women’s Health Questionnaire. Acta Obstet Gynecol Scand 1993;72:648 /55. [7] Ware JE, Kosinski M, Keller SD. SF-36 physical and mental health summary scales: a user’s manual. Boston, MA: The Health Institute, New England Medical Center, 1994. [8] Badia X, Roset M, Herdman M, Kind P. A comparison of United Kingdom and Spanish general population time trade-off values for EQ-5D health states. Med Decision Making 2001;21:7 /16. [9] Sowers MF. The menopause transition and the aging process: a population perspective. Aging (Milano) 2000;12(2):85 /92. [10] Blumel JE, Castelo-Branco C, Binfa L, Gramegna G, Tacla X, Aracena B, Cumsille MA, Sanjuan A. Quality of life after the menopause: a population study. Maturitas 2000;34(1):17 /23. [11] Dennerstein L, Helmes E. The menopausal transition and quality of life: methodological issues. Quality Life Res 2000;9:721 /31.
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[12] Hilditch JR, Lewis J, Ross AH, Peter A, Van Maris B, Franssen E, Charles J, Norton P, Dunn EV. A comparison of the effects of oral conjugated equine estrogen and transdermal estradiol-17 beta combined with an oral progestin on quality of life in postmenopausal women. Maturitas 1996;24(3):177 /84. [13] Bech P, Munk-Jensen N, Obel EB, Ulrich LG, Eiken P, Nielsen SP. Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures. Psychother Psychosom 1998;67(4 /5):259 /65. [14] Derman RJ, Dawood MY, Stone S. Quality of life during sequential hormone replacement therapy: a placebo-controlled study. Int J Fertil Menopausal Stud 1995;40(2):73 / 8. [15] Karlberg J, Mattsson LA, Wiklund I. A quality of life perspective on who benefits from estradiol replacement therapy. Acta Obstet Gynecol Scand 1995;74(5):367 /72. [16] Wiklund I, Berg G, Hammar M, Karlberg J, Lindgren R, Sandin K. Long-term effect of transdermal hormonal therapy on aspects of quality of life in postmenopausal women. Maturitas 1992;14(3):225 /36. [17] Rebar RW, Trabal J, Mortola J. Low-dose esterified estrogens (0.3 mg/day): long-term and short-term effects on menopausal symptoms and quality of life in postmenopausal women. Climacteric 2000;3(3):176 /82. [18] Wiklund I, Karlberg J, Mattsson LA. Quality of life of postmenopausal women on a regimen of transdermal estradiol therapy: a double-blind placebo-controlled study. Am J Obstet Gynecol 1993;168(3 Pt 1):824 /30. [19] Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol 1991;78(6):991 /5.
Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women Marco Gambacciani *, Massimo Ciaponi, Barbara Cappagli, Patrizia Monteleone, Caterina Benussi, Gemma Bevilacqua, Andrea R. Genazzani Department of Obstetrics and Gynecology, University of Pisa, Via Roma 67, 56100 Pisa, Italy Received 20 February 2002; received in revised form 19 September 2002; accepted 24 October 2002
Abstract Objectives: To describe the effects of low dose hormonal replacement therapy (LD-HRT) on quality of life in early postmenopausal women, since the postmenopausal estrogen deprivation in mid age women often brings along a series of changes and symptoms, which may greatly affect quality of life. Methods: Fifty normal postmenopausal women were recruited and randomly treated with LD-HRT, 17b-estradiol (1 mg/day) and norethisterone acetate (0.5 mg/day) (LDHRT) or calcium supplement (controls). No significant differences in age, age at menopause, the presence of chronic diseases and socio-economic status were present in the two groups. The Women’s Health Questionnaire (WHQ), a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and after 6 and 12 weeks of treatment in both groups. Results: At baseline no significant differences in WHQ scores were present in the two groups. In the control group the scores in all different areas showed no significant modification either after 6 and 12 weeks of observation. Conversely, the LD-HRT group showed a significant decrease in the scores of vasomotor symptoms, somatic symptoms, anxiety/fear, depressed mood and sleep problem items. No effects on memory/concentration and menstrual symptoms areas were evident. Conclusion: Although quality of life is also and may be mainly influenced by socio-economic and cultural factors, LD-HRT definitively can improve not only vasomotor symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estradiol; Noretisterone acetate; Hormonal replacement therapy; Quality of life
1. Introduction * Corresponding author. Tel.: /39-50-992385; fax: /39-50553410 E-mail address: [email protected] (M. Gambacciani).
Nowadays, quality of life (QoL) is an important outcome that reflect the way patients feel and function. The menopause transition in mid age
0378-5122/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 3 2 7 - 4
158
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
women often brings along mood alterations, sleeplessness, hot flushes and sweats, sexual dysfunction, the impact of which may be noteworthy on the QoL. Thus, QoL evaluation can be considered an essential component to provide a comprehensive picture of the effect of the menopause and to assess the possible benefits of different treatments. To this end, different scales have been used to evaluate QoL in postmenopause [1 /8]. Recently the Italian version of the Women’s Health Questionnaire (WHQ) has been validated in an Italian population of menopausal women, with results sustaining the use of WHQ to investigate QoL in Italian postmenopausal women population [5]. In this study the item /scale correlations, used to evaluate item-internal consistency, exceeded the minimum accepted value of 0.30 for all items with the exception of three, two relative to depression (item 10, r /0.15 and item 07, r / 0.22) and one to somatic symptoms (item 23, r / 0.24). The item-discriminant validity was measured by the scaling success rate, that is the percentage of times items correlated significantly higher with its corrected scale score than with other scale scores in the instrument. The scaling success rate was high for all the scales, ranging between 83 and 100%. In particular, for vasomotor symptoms, sexual behavior and menstrual symptoms the correlation between an item and its hypothesized scale always exceeded correlations with all other scales [5]. Also the reliability of scale scores was exellent. For seven out of nine scales the Chronbach alpha coefficient was in the range of 0.6 /0.7 (for group comparisons, a minimum value of 0.5 [9,10] to 0.7 [11] is generally recommended). For two scales, i.e. menstrual symptoms and attractiveness, the internal-consistency reliability indexes were less satisfactory. Chronbach alpha coefficient for the summary scale, composed of 35 items, was 0.88. Test /retest reliability was excellent, with coefficients largely exceeding the value of 0.70 for all the scales [5]. The perception of QoL is significantly modified during the peri/ postmenopausal period [9 /11]. Hormone replacement therapy (HRT) can be used to reverse or improve climacteric symptoms, and to maintain the physical and psychological day-to-day functioning of the postmenopausal woman [12 /16].
However, until now, scarce information is available on the possible effects of low dose hormonal replacement therapy (LD-HRT) on QoL [17]. The aim of this longitudinal study was to describe the effects of LD-HRT on QoL in a group of early postmenopausal women and compare their outcome in term of QoL with untreated similar postmenopausal women group.
2. Materials and methods Ethical Committee of our Department approved the study protocol. Fifty postmenopausal women were recruited and assigned to LD-HRT or calcium /vitamin treated group (control group), using a randomisation list (yes /no). The LD-HRT group received a daily pill containing 1 mg estradiol/0.5 mg noretisterone acetate each pill (ActivelleTM, Novo Nordisk) for 28 days on 28. The control group receiving a daily supplement of calcium (1000 mg/day). QoL was evaluated by a questionnaire (the WHQ) handed to the women during a visit to the centre. The WHQ was developed in England to investigate psychological and somatic symptoms experienced by peri and postmenopausal women [1,4 /6], and its psychometric properties have already been well documented [1,4 /6]. The questionnaire is composed of 36 questions rated on four-point scales, indicating the extent to which symptoms or sensations are experienced. The higher the score, the more pronounced is the distress and dysfunction. The 36 items are combined into nine subscales describing somatic symptoms (seven items), depressed mood (seven items), memory/concentration difficulties (three items), anxiety/fears (four items), sexual behavior (three items), vasomotor symptoms (two items), sleep problems (three items), menstrual symptoms (four items) and attractiveness (two items). The cultural adaptation of the WHQ into Italian has been performed by the Mapi Research Institute, Lyon, France. The forward/backward method was employed to ensure conceptual equivalence. Briefly, a QoL specialist was recruited as project manager and WHQ was translated from English to Italian by two independent professional transla-
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
tors, native Italian language speakers and bilingual in the source language. The two versions were reviewed with the translators and the project manager and an agreement was reached for a pre-final Italian version of the questionnaire. A backward translation (from Italian to English) was performed by a professional translator, English native speaker and bilingual in the target language. The agreed final English translation was thus evaluated by the originator of the WHQ (M. Hunter) who gave her approval to the use of the Italian version of the questionnaire. The WHQ was already validated in a large Italian population of pre, peri and postmenopausal women and was shown to be a valid, reliable and reproducible instrument [5]. The questionnaire was anonymous, filled in at home and then returned at each visit to the centre. For each enrolled woman, the gynaecologist collected socio-demographic and clinical data on ad hoc forms. Each questionnaire was matched with the clinical data by a code present on both forms. No significant differences in age, years since menopause (YSM), body mass index (BMI), Follicle-stimulating-hormone (FSH), Estradiol plasma levels and socioeconomic level were found between the two groups (Tables 1 and 2). Moreover, the two groups of women were free from chronic diseases (cancer, cardiovascular disease, depression treated with drugs and other serious concomitan pathologies) and socio-economic problems (Table 2) known to affect QoL. All the 50 women recruited in the study filled in the questionnaire (25 of the LD-HRT group and 25 of Table 1 Control group, postmenopausal women receiving 1000 mg of calcium per day (n /25); LD-HRT, postmenopausal women receiving oral pill contain 1 mg estradiol/0.5 mg noretisterone acetate per day (n /25)
Age (year) YSM BMI (kg/m2) FSH (IU/l) Estradiol (pg/ml)
Control
LD-HRT
54.39/0.3 4.59/0.7 24.59/0.9 85.49/7.8 18.49/2.3
54.49/0.5 4.79/0.5 24.19/0.5 81.59/4.5 20.29/3.4
YSM, years since menopause; BMI, body mass index; FSH, follicle-stimulating hormone.
159
Table 2 General characteristics of women in control group, postmenopausal women receiving 1000 mg of calcium per day (n /25); and LD-HRT, postmenopausal women receiving oral pill contain 1 mg estradiol/0.5 mg noretisterone acetate per day (n /25) Control
LD-HRT
School education 0 /8 years 9 /13 years /13 years
11 (44%) 11 (44%) 3 (12%)
10 (40%) 10 (40%) 5 (20%)
Occupation Employed Retired Housewife Unemployed
10 (40%) 5 (20%) 10 (40%) 0 (0%)
11 (44%) 5 (20%) 9 (36%) 0 (0%)
Marital status Single Married Widowed/divorced
1 (4%) 24 (96%) 0 (0%)
2 (8%) 23 (92%) 0 (0%)
Social class Middle class Working class
10 (40%) 15 (60%)
10 (40%) 15 (60%)
untreated group; response rate 100%). The questionnaire was performed at baseline, after 6 and 12 week of study. QoL was investigated by using a questionnaire specifically designed to evaluate the impact of menopausal symptoms. All the results are reported as the Mean9/S.E. of absolute values. Baseline values were compared by Student’s t -test. Two way analysis of variance for repeated measures and factorial analysis of variance were used to test the differences within and between the groups, respectively. The post-hoc comparison was made by Scheffe F -test.
3. Results No significant differences in age, YSM, BMI, FSH and Estradiol plasma levels were present in the two groups (Table 1). Basal scores in the different nine subscales were similar in the two groups (Figs. 1 /3). In the LD-HRT treated group a significant (P B/0.05) decrease from baseline values in the scores of six out of nine of the WHQ domains was evident after 6 and 12 weeks of
160
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
Fig. 1. Depressed mood, Somatic symptoms and memory/concentration items (mean9/S.E.) at baseline (0 weeks), 6, and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
treatment (Figs. 1 /3). The scores improvement included vasomotor symptoms, sexual behaviour, depressed mood, somatic symptoms, anxiety/fear and sleep problem items (Figs. 1/3). In addition, all of the items mentioned above showed a significant difference (P B/0.05) between LDHRT and control group after 12 weeks of study. A particular feature is shown by vasomotor symptoms item that presented a significant (P B/ 0.05) difference between LD-HRT and control group till from the sixth week of observation (Fig. 2). On the contrary, no statistically significant differences within the LD-HRT treated group and between this group and the control group were found for memory concentration, menstrual symptoms and attractiveness items (Figs. 1 and 3, respectively). Also the women of control group showed an improvement for some items (somatic symptoms, memory/concentration, vasomotor symptoms, anxiety/fear, sleep problem) (Figs. 1/
3). The improvement reaches the peak (but not the statistical significance) around the sixth week of treatment and than decline (Figs. 1/3). However, after 12 weeks of treatment, the changes in the control group were less pronounced that those observed in LD-HRT treated group and did not reach statistical significance (Figs. 1 /3).
4. Discussion This is the first longitudinal randomized trial showing the effects of low dose HRT on QoL in early menopausal women. Present data show that short term LD-HRT can improve QoL in symptomatic women. Wiklund et al. [18] in a noncomparative Swedish study also showed that the quality of life of menopausal women improved after treatment with Estraderm TTS to a level comparable to that of a nonmenopausal reference
M. Gambacciani et al. / Maturitas 44 (2003) 157 /163
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Fig. 2. Vasomotor symptoms, anxiety/fear and sexual behaviour items (mean9/S.E.) at baseline (0 weeks), 6 and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
group. Ditkoff et al. [19] demonstrated the improvement of psychologic functions in asymptomatic women by means of estrogen unaccompanied by progestogen. Although the instruments used by Ditkoff et al. were not specific to the assessment of quality of life, the authors themselves suggested that their results indicate a beneficial effect of unopposed estrogen on quality of life. These studies confirm that the effect of estrogen on quality of life is not merely caused by its clinical efficacy on vasomotor symptoms, as shown by its effectiveness, regardless of the presence or absence of the flushes [19]. Perceptions of well-being in healthy, postmenopausal women depend not only on biological changes experienced as consequence of estrogen deprivation, but also on socio-economic circumstances, individual cultural and personal experiences [5]. In this way, the effects observed after such a short term observation can not be ascribed
to relevant variation in socioeconomic or cultural status of LD-HRT treated women. LD-HRT users showed a significantly better QoL almost in all the symptoms scores of the WHQ, with the only exceptions of menstrual symptoms, memory/concentration and attractivness. In particular, LD-HRT users showed a lower probability of reporting anxiety/fears (Fig. 2). When looking at menopause symptoms, LDHRT users showed highly significant better outcomes in those areas which are more directly attributable to hormonal changes of mid age, namely vasomotor symptoms and sexual problems (Fig. 2). The overall picture emerging from this analysis suggests that HRT can be of benefit for many of the postmenopausal mood changes, sexual problems and vasomotor symptoms (Figs. 1 and 2), while untreated women show no significant alteration in the incidence of the disturbs investigated by the nine items (Figs. 1 /3).
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Fig. 3. Sleep problems, menstrual symptoms and Attractiveness items (mean9/S.E.) at baseline (0 weeks), 6 and 12 weeks in early postmenopausal women in calcium-treated control group (n /25) and in the LD-HRT group (n /25). *P B/0.05 vs. corresponding baseline levels; #P B/0.05 vs. corresponding control group values.
In future studies the assessment of QoL will be an essential tool along with clinical and laboratory evaluation, for estimating the efficacy of therapy. The great majority of the larger trials had some possible limitation depends on the cross-sectional nature of the design, which can only indicate whether associations exist, but does not allow determining the direction of causality. Indeed our study represents a small sample of postmenopausal women, but the longitudinal nature of the research makes it quite interesting. Our study shows that also LD-HRT has the potential of improving not only symptoms, but also more general aspects of physical and psychological well-being, minimizing the side effects correlated to hormone use, at least at the standard doses actually used. Further therapeutic strategies should take into account that at a time, when mid-aged women are both culturally aware of the negative aspects
related to the menopause and need to maintain a good level of social and physical functioning, patient-centered evaluation is more and more important, in order to be able to provide information on how the treatments proposed affect different aspects of QoL. The demonstration of efficacy of LD-HRT furnishes us an additive tool in the field of postmenopausal correlated syndrome treatment.
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