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Urogenital and vasomotor symptoms in relation to menopausal status and the use of hormone replacement therapy (HRT) in healthy women during transition to menopause
Maturitas 28 (1997) 99 – 105
Urogenital and vasomotor symptoms in relation to menopausal status and the use of hormone replacement therapy (HRT) in healthy women during transition to menopause B. Larson a,*, A. Collins b, B.-M. Landgren a a
Department of Woman and Child Health, Di6ision for Obstetrics and Gynecology, Karolinska Hospital, S-171 76 Stockholm, Sweden b Department of Clinical Neuroscience, Psychiatry and Psychology Section, Karolinska Hospital, Stockholm, Sweden Received 17 March 1997; received in revised form 28 August 1997; accepted 4 September 1997
Abstract Objective: To investigate the relationship between climacteric status, hormonal levels, vasomotor symptoms, vaginal dryness and urinary incontinence in a cohort of healthy women during transition to menopause, and further to evaluate the effects of hormone replacement therapy on these symptoms. Methods: A total of 147 women were followed for 4 years during transition to menopause. They were all 49 years old when entering the study. Each annual visit included a general health screening, gynecological examination and blood sampling. The subjects were questioned about sociodemographic background, obstetric and gynecological history and they kept bleeding diary cards. Results: Urinary incontinence was reported by 57% at the first visit and decreased to 34% at the last visit. No correlation to hormonal levels or to the use of HRT (hormone replacement therapy) was seen, but parity was significantly (P =0.05) correlated to urinary incontinence. Vaginal dryness occurred in 37% at the first visit. Vaginal dryness was experienced by 1/3 of the premenopausal women. Vasomotor symptoms were reported by 56% at the first visit and were associated with high levels of FSH and LH (P B0.001 and P = 0.002, respectively). One third of premenopausal women reported on vasomotor symptoms. Hormone replacement therapy did not relieve hot flushes in these women. Conclusions: Urogenital and vasomotor symptoms experienced by premenopausal women do not seem to be relieved by hormone replacement therapy. © 1997 Elsevier Science Ireland Ltd. Keywords: Menopause; Hormone replacement therapy; Urogenital; Vasomotor
* Corresponding author. Tel.: +46 8 7292000; fax: + 46 8 318114. 0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 7 8 - 5 1 2 2 ( 9 7 ) 0 0 0 6 8 - 6
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B. Larson et al. / Maturitas 28 (1997) 99–105
1. Introduction
2. Subjects and method
The years before menopause, often referred to as menopausal transition, is a period of increasing ovarian failure characterized by fluctuating and decreasing reproductive hormonal secretion. These hormonal changes are known to vary between individuals and over time [1 – 3]. The symptoms most often associated with menopausal transition are bleeding irregularities, vasomotor and urogenital symptoms. Studies of the prevalence of urogenital symptoms are few and the results divergent. Whether these symptoms are dependent on estrogen deficiency or ageing is under debate. Molander [4] concluded that the prevalence of urinary incontinence does not increase as a function of menopause. It is true that many women are reluctant to admit urinary incontinence. Thus, the magnitude of the problem is probably under-estimated. The use of estrogen therapy for the relief of incontinence is controversial [5]. Most studies on the occurrence of climacteric symptoms and the effects of hormonal treatment have been performed in women seeking medical advice. More recently, a number of studies have dealt with healthy women during menopausal transition. These studies have mainly been crosssectional in design [6,7]. The few recent longitudinal investigations have used mail questionnaires or telephone interviews, which may introduce bias in remembering climacteric problems, the occurrence of symptoms and treatment effects [8 – 11]. A number of studies relating hormonal changes to the occurrence of vasomotor symptoms have found correlations between FSH and estradiol levels and hot flushes for groups of women [1,2]. Menstrual bleeding pattern has also been correlated to hormonal changes during transition to menopause [1,2]. The aim of this study was to investigate the relationship between climacteric status, hormonal levels, hot flushes, vaginal dryness and urinary incontinence. A second aim was to evaluate the effect of hormone replacement therapy (HRT) on these symptoms in a cohort of healthy women during transition to menopause.
The earlier phase of the population based study of 1399 healthy women, who were recruited through the Swedish population register, was based on a questionnaire completed by the women about their reproductive health, use of estrogen and experience of climacteric symptoms [12]. Out of these 1399 women, a random stratified sample reflecting educational level and parity was drawn. This sample included 161 women who received an invitation to participate in a longitudinal study including a somatic, gynecological part as well as a psychological part. To be eligible for the study, the women had to be healthy, menstruating and to be non-users of hormone replacement. The women were 49 years old when entering the study and they were followed thereafter annually for a total of 4 years. Each annual visit included a general health screening, gynecological examination and blood sampling. At the first visit to the Department of Woman and Child Health, they were asked questions about sociodemographic background such as marital status, education, occupation, number of children and smoking habits. In addition, questions were asked about obstetric and gynecological history and use of contraception. At each visit the women were asked in detail about their bleeding. They were instructed to keep bleeding diary cards. Questions about hormone replacement therapy and experience of climacteric symptoms were also asked.
2.1. Climacteric status The women were assigned to three different categories with regard to climacteric status. The presence of mainly regular periods was defined as premenopausal status. Irregular bleeding or absence of bleeding for less than 12 months was classified as perimenopausal, and absence of bleeding for more than 12 months as postmenopausal. Women using hormone replacement therapy (HRT) constituted a separate group. During the study, HRT was prescribed to women who requested it. Some women had obtained a prescription from other doctors.
B. Larson et al. / Maturitas 28 (1997) 99–105
2.2. Hormonal analyses Circulating levels of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone and prolactin in serum were measured by radioimmunoassay methods using commercial kits (Diagnostic Products Corporation, LA).
2.3. Statistical methods Differences in distributions between groups were tested with the x 2 statistic and between means with the student’s t-statistic. Correlation analysis was carried out with Pearson’s product moment correlation. Survival analysis was applied to menopause status data, where time to menopause was treated in the same way as time to death in ordinary survival analysis. The log rank test was used to test differences between groups The study was approved by the Ethics Committee of the Karolinska hospital.
3. Results Out of 161 women invited, 151 (94%) came to the first visit. Four women dropped out during the study. All four visits were attended by 147 (91%) women. A total of nine women had reached menopause during the period from recruitment to the first visit and ten women had started HRT. During the 4 years of observation, nine women underwent hysterectomy and bilateral salpingooophorectomy, four because of myomas, three endometrial cancer, one ovarian cancer and one endometriosis. These women were excluded from further analyses.
3.1. Background In Table 1 and Table 2 background data are given. The majority of the women were married. The educational level of the women reflects that of the original population of 1399 women. Seventy three percent worked full time and 27% part time, the majority being employed in intermediary level jobs; 26% had professional jobs, 10% were
101
Table 1 Some sociodemographic characteristics Sociodemographic characteristics
Number (n)
Marital status Single 7 Married 115 Divorced 22 Widow 3 Education Primary 44 Secondary 54 College 49 Employment Full-time 107 Part-time 40 Occupation Higher professionals 15 Lower professionals 38 Service or clerical jobs 81 Unskilled jobs 12 House-wife 1 Smokers 33
Percentage (%)
5 78 15 2 30 37 33 73 27 10 26 55 8 1 22
executives or managers, 8% were employed in unskilled jobs and 1% were housewives. Ninety percent of the women had children; 47% had two children, which corresponds to the Swedish national average number [13], 10% were childless. Previous fertility problems were experienced by 16%. Questions concerning contraception were only asked when the women were 49 years old. A considerable percentage (61%) reported the use of some form of contraception. Table 2 Reproductive characteristics Reproductive characteristics Number of children 0 1 2 3 \4 Infertility Miscarriage/abortion Contraceptive users BMI*
Number (n)
Percentage (%)
15 25 69 35 3 24 53 90 23.7 (96.7)
10 17 47 24 2 16 36 61
* Expressed as [weight (kg)/height2 (m)]×100.
B. Larson et al. / Maturitas 28 (1997) 99–105
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Table 3 Distribution of menopausal status in relation to consecutive visits (V1 – V4)
Menopausal status Premenopausal Perimenopausal Postmenopausal HRT Hyst
V1 72 56 9 10 0
Visit V2 56 46 18 26 1
V3 8 58 17 58 6
V4 10 29 22 77 9
3.2. Transition to menopause The distribution of climacteric status over time is shown in Table 3. The number of premenopausal women decreased from 72 at first visit to ten at the fourth visit. The number of perimenopausal women was diminished from 56 to 29 during the study period and 22 women were postmenopausal at the fourth visit. Since two women reported irregular periods at visit 3, they were categorized as perimenopausal. At the fourth visit, they had regular periods and were classified as premenopausal. The number of women using HRT was 77 (53%) at visit 4. As could be expected, estradiol decreased significantly during transition to menopause and LH and FSH increased. There was no significant change in prolactin levels. FSH and LH levels at the first visit were strong predictors of menopause. Menstruating women with the highest levels of FSH and LH had their last menstruation significantly earlier than those with lower levels.
Table 4 Symptoms reported (%) at each visit
Vasomotor Vaginal dryness Urine incontinence Rate of stress incontinence
1
Visit 2
3
4
56 37 57 —
61 18 37 90
36 19 34 75
45 27 34 81
3.3. Symptoms The symptoms reported by the women at each visit are shown in Table 4. The consistency over time was greatest for urine incontinence which was reported by 57% at the first visit and 34% at visits 3 and 4, 15% of those moderate or severe. The correlation coefficient varied between 0.51 and 0.69 (PB 0.001) when measured between two adjacent occasions. No correlation between incontinence and hormone levels nor with other symptoms was found. On the other hand, incontinence was associated with parity and there was a trend of increasing prevalence with each child born (P(trend) = 0.02). The main difference was between nulliparous and parous women (P= 0.012). HRT did not have any effect on urinary symptoms. Vaginal dryness was reported by 37% at the first visit, only 6% having moderate to severe complaints. A total of 1/3 of the women were premenopausal. The symptoms did not correlate with hormone levels or the occurrence of vasomotor symptoms. When measured between two adjacent occasions, the correlation coefficients were 0.41– 0.50 (PB 0.001). Vasomotor symptoms varied most between visits with a correlation coefficient varying between 0.26 and 0.46 (PB 0.002). Hot flushes and sweating were significantly associated with high levels of FSH and LH (PB 0.001 and P=0.002, respectively) and with low levels of estradiol (P= 0.045). Women using HRT presented with the same rate of vasomotor symptoms as women not using HRT at the first two visits. At visits 3 and 4, however, women on HRT reported significantly less vasomotor symptoms than women without. The rate of vasomotor symptoms before and after initiation of HRT by time is shown in Fig. 1. At the first visit, while the women were still menstruating, the indication for HRT was predominantly vasomotor symptoms, which persisted at visit 2. At visits 2, 3 and 4 the proportion of women prescribed HRT due to vasomotor symptoms decreased in favour of other indications, such as prophylaxis for osteoporosis, vaginal dryness, sleeping disturbances and memory dysfunction. The positive effects of HRT increased at visits 2 and 3, but were slightly decreased at visit
B. Larson et al. / Maturitas 28 (1997) 99–105
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Fig. 1. Rate of vasomotor symptoms before and after initiation of HRT: (A) women prescribed HRT at first visit; (B) women prescribed HRT at second visit; (C) women prescribed HRT at third visit.
4, indicating a placebo effect. Only six women discontinued their therapy during the study. Cigarette smoking was not associated with hormonal levels nor with menopausal status or vasomotor symptom.
4. Discussion More than 50% of the women reported urinary incontinence at the first visit. It should be pointed out that this figure includes all types of incontinence. Moderate or severe incontinence was reported by 15%. The prevalence of urinary incontinence varies between studies, depending on age of the subjects and definition of the symptoms. The highest rates reported were 50 and 73% [14,15]. A prevalence peak of urinary incontinence around the menopause has been reported by Thomas et al. [16] and Jolleys [17]. In our study, urine leakage declined from 57% at the first visit to about 35% at the following three visits, due to a reduction of stress incontinence, in agreement with Holst and Wilson [18] and Reekers et al. [19]. An explanation might be that the women have received advice regarding pelvic muscle training
by the doctor in charge. No correlation between incontinence and hormonal levels nor with other symptoms or the use of HRT was found. This therefore suggests that menopause may not be crucial for the occurrence of these symptoms. On the other hand, incontinence was associated with parity. Thus, parity seems to be more important than climacteric-status for incontinence, which is in agreement with findings of Molander [4]. Vaginal dryness was reported by 35% of the women at the first visit, only 6% having moderate or severe complaints. No correlation to hormonal levels or to other symptoms was found. Vaginal dryness occurs most frequently 4–6 years after menopause [20] and is then related to low endogenous plasma levels of estrogens [21,22]. In our study, this symptom was at the first visit reported by 1/3 of the premenopausal women. The experience of vaginal dryness in our women is therefore probably not associated with vaginal atrophy of the epithelium due to estrogen deficiency, but can be explained by other factors such as relationship with partner. The frequency of vasomotor symptoms was about 60% at the first two visits and 1/3 of the premenausal women reported this symptom at
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each visit. The incidence of hot flushes in women around menopause is reported to be as high as 80% [23,24]. In a Swedish study [7], 44% of women aged 52–54 years reported moderate to severe vasomotor symptoms. It is also well known that a certain percentage of women experience hot flushes many years before menopause [9,25]. More than 1/2 of the women were using HRT at the last visit. The use of HRT in Sweden has increased 3-fold from 1990 – 1996 [26]. Furthermore, the indications for HRT have been expanded to include prophylaxis of osteoporosis which was accepted in 1992. It has been known that women who have regular contacts with medical practitioners are more likely to be using HRT [27]. In our study, the women saw a gynecologist annually, which could partly explain the high rate of HRT use, although women were only prescribed HRT on request. Today, there is an increasing tendency of women to start HRT while still menstruating. In a Danish study [28], 22% of the women 51 years of age used HRT, 42% of those had started during the premenopause; 40% discontinued HRT and reported no effect as reason for discontinuing. The mechanism behind hot flushes is not yet fully understood. Even if vasomotor symptoms are correlated to low estrogen levels in groups of women, neither estrogen deficit nor elevated gonadotropin levels have been linked to the initiation of a hot flush in the individual woman [29]. Thus, there is no rationale for treating hot flushes with estrogen in women who still menstruate and thus do not have low endogenous estrogen levels. This must be taken into consideration before prescribing HRT to premenopausal women. Acknowledgements We are grateful to Bo Nilsson for statistical calculations of the results of this study. References [1] Metcalf MG, Donald RA, Livesey JH. Pituitary-ovarian function in normal women during the menopausal transition. Clin Endocrinol 1981;14(3):245–55.
[2] Korenman SG, Sherman BM, Korenman JC. Reproductive hormone function: the perimenopausal period and beyond (review). Clin Endocrinol Metab 1978;7(3):625 – 43. [3] Burger HG. The endocrinology of the menopause (review). Maturitas 1996;23:129 – 36. [4] Molander U. Urinary incontinence and related urogenital symptoms in elderly women. Acta Obstet Gynecol Scand 1993;158:1 – 22. [5] Cardozo LD, Kelleher CJ. Sex hormones, the menopause and urinary problems. Gynecol Endocrinol 1995;9(1):75 – 84. [6] Dennerstein L, Smith AM, Morse C. Psychological wellbeing, mid-life and menopause. Maturitas 1994;20:1 – 11. [7] Hammar M, Berg G, Fa˚hreus L, Larsson-Cohn U. Climacteric symptoms in an unselected sample of Swedish women. Maturitas 1984;6:345 – 50. [8] Holte A, Mikkelsen A. The menopausal syndrome: a factor analytic replication. Maturitas 1991;13:193 – 203. [9] Hunter M. The South-East England longitudinal study of the climacteric and postmenopause. Maturitas 1992;14:117 – 26. [10] Kaufert PA, Gilbert P, Hassard T. Researching the symptoms of menopause: an exercise in methodology. Maturitas 1988;10:117 – 31. [11] McKinley SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103 – 15. [12] Collins A, Landgren BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101 – 11. [13] Statistiska Centralbyra˚n. Folk-och bostadsra¨kningen 1990. Stockholm, Sweden. (statistical information on the Swedish population). Swedish text. [14] Yarnell JWG, Voile GJ, Richards CJ, Stephensen TP. The prevalence and severity of urinary incontinence in women. J Epidemiol Community Health 1981;35:71 – 4. ˚ , Heimer G, Ulmsten U, Cnattingius S. Preva[15] Stenberg A lence of genitourinary and other climacteric symptoms in 61 year old women. Maturitas 1996;24:31 – 6. [16] Thomas TM, Plymat KR, Blannin J, Meade TW. Prevalence of urinary incontinence. Br Med J 1981;281:1243– 5. [17] Jolleys JV. Reported prevalence of urinary incontinence in women in a general practice. Br Med J 1988;296:1300– 2. [18] Holst K, Wilson PD. The prevalence of female urinary incontinence and reasons for not seeking treatment. New Zealand Med J 1988;101:756 – 8. [19] Rekers H, Drogendijk HA, Valkenburg RF. The menopause, urinary incontinence and other symptoms of the genito-urinary tract. Maturitas 1992;15:101 – 11. [20] Berg G, Gottgall T, Hammar M, Lindgren R. Climacteric symptoms among women aged 60 – 62 in Linko¨ping, Sweden, in 1986. Maturitas 1988;10:193 – 9. [21] Morse A, Hutton J, Jacobs H, Murray M, James V. Relation between the karyopycnotic index and plasma oestrogen concentration after the menopause. Br J Obstet Gynaecol 1979;86:981.
B. Larson et al. / Maturitas 28 (1997) 99–105 [22] Nilsson K, Heimer G. Endogenous estrogen levels in postmenopausal women with severe urogenital atrophy. Gynecol Obstet Invest 1992;34:234–6. [23] Ballinger SE. Psychosocial stress and symptoms of menopause; a comparative study of menopause clinic patients and non patients. Maturitas 1985;7:315–27. [24] Oldenhave A, Jaszmann LJB. The climacteric absence or presence of hot flushes and their relation to other complaints. In: Schonbaum E, editor. The Climacteric Hot Flush. Prog Basic Clin Pharmacol. Basel: Karger 1991;6:1 – 39. [25] Hagstad, A. Gynecology and sexuality of the mature woman. An epidemiological study. Doctoral thesis, University of Gothenburg, Sweden, 1985.
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[26] Svensk La¨kemedelsstatistik. Nordenstam I, Wennberg M, Kristoferson K, editors. Stockholm: Apoteksbolaget 1994:130 – 134. (Swedish text) [27] Shelley JM, Smith AMA, Dudley E, Dennerstein L. Use of hormone replacement therapy by Melbourne women. Aust J Public Health 1995;19:387 – 92. [28] Ko¨ster A. Hormone replacement therapy: use patterns in 51 year old Danish women. Maturitas 1990;4:345 – 56. [29] Ginsburg J, Hardiman P. The menopausal hot flush; facts and fancies. In: Berg G, Hammar M, editors. The Modern Management of Menopause. Lancaster: Parthenon, 1994;123 – 135.
Urogenital and vasomotor symptoms in relation to menopausal status and the use of hormone replacement therapy (HRT) in healthy women during transition to menopause B. Larson a,*, A. Collins b, B.-M. Landgren a a
Department of Woman and Child Health, Di6ision for Obstetrics and Gynecology, Karolinska Hospital, S-171 76 Stockholm, Sweden b Department of Clinical Neuroscience, Psychiatry and Psychology Section, Karolinska Hospital, Stockholm, Sweden Received 17 March 1997; received in revised form 28 August 1997; accepted 4 September 1997
Abstract Objective: To investigate the relationship between climacteric status, hormonal levels, vasomotor symptoms, vaginal dryness and urinary incontinence in a cohort of healthy women during transition to menopause, and further to evaluate the effects of hormone replacement therapy on these symptoms. Methods: A total of 147 women were followed for 4 years during transition to menopause. They were all 49 years old when entering the study. Each annual visit included a general health screening, gynecological examination and blood sampling. The subjects were questioned about sociodemographic background, obstetric and gynecological history and they kept bleeding diary cards. Results: Urinary incontinence was reported by 57% at the first visit and decreased to 34% at the last visit. No correlation to hormonal levels or to the use of HRT (hormone replacement therapy) was seen, but parity was significantly (P =0.05) correlated to urinary incontinence. Vaginal dryness occurred in 37% at the first visit. Vaginal dryness was experienced by 1/3 of the premenopausal women. Vasomotor symptoms were reported by 56% at the first visit and were associated with high levels of FSH and LH (P B0.001 and P = 0.002, respectively). One third of premenopausal women reported on vasomotor symptoms. Hormone replacement therapy did not relieve hot flushes in these women. Conclusions: Urogenital and vasomotor symptoms experienced by premenopausal women do not seem to be relieved by hormone replacement therapy. © 1997 Elsevier Science Ireland Ltd. Keywords: Menopause; Hormone replacement therapy; Urogenital; Vasomotor
* Corresponding author. Tel.: +46 8 7292000; fax: + 46 8 318114. 0378-5122/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 7 8 - 5 1 2 2 ( 9 7 ) 0 0 0 6 8 - 6
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B. Larson et al. / Maturitas 28 (1997) 99–105
1. Introduction
2. Subjects and method
The years before menopause, often referred to as menopausal transition, is a period of increasing ovarian failure characterized by fluctuating and decreasing reproductive hormonal secretion. These hormonal changes are known to vary between individuals and over time [1 – 3]. The symptoms most often associated with menopausal transition are bleeding irregularities, vasomotor and urogenital symptoms. Studies of the prevalence of urogenital symptoms are few and the results divergent. Whether these symptoms are dependent on estrogen deficiency or ageing is under debate. Molander [4] concluded that the prevalence of urinary incontinence does not increase as a function of menopause. It is true that many women are reluctant to admit urinary incontinence. Thus, the magnitude of the problem is probably under-estimated. The use of estrogen therapy for the relief of incontinence is controversial [5]. Most studies on the occurrence of climacteric symptoms and the effects of hormonal treatment have been performed in women seeking medical advice. More recently, a number of studies have dealt with healthy women during menopausal transition. These studies have mainly been crosssectional in design [6,7]. The few recent longitudinal investigations have used mail questionnaires or telephone interviews, which may introduce bias in remembering climacteric problems, the occurrence of symptoms and treatment effects [8 – 11]. A number of studies relating hormonal changes to the occurrence of vasomotor symptoms have found correlations between FSH and estradiol levels and hot flushes for groups of women [1,2]. Menstrual bleeding pattern has also been correlated to hormonal changes during transition to menopause [1,2]. The aim of this study was to investigate the relationship between climacteric status, hormonal levels, hot flushes, vaginal dryness and urinary incontinence. A second aim was to evaluate the effect of hormone replacement therapy (HRT) on these symptoms in a cohort of healthy women during transition to menopause.
The earlier phase of the population based study of 1399 healthy women, who were recruited through the Swedish population register, was based on a questionnaire completed by the women about their reproductive health, use of estrogen and experience of climacteric symptoms [12]. Out of these 1399 women, a random stratified sample reflecting educational level and parity was drawn. This sample included 161 women who received an invitation to participate in a longitudinal study including a somatic, gynecological part as well as a psychological part. To be eligible for the study, the women had to be healthy, menstruating and to be non-users of hormone replacement. The women were 49 years old when entering the study and they were followed thereafter annually for a total of 4 years. Each annual visit included a general health screening, gynecological examination and blood sampling. At the first visit to the Department of Woman and Child Health, they were asked questions about sociodemographic background such as marital status, education, occupation, number of children and smoking habits. In addition, questions were asked about obstetric and gynecological history and use of contraception. At each visit the women were asked in detail about their bleeding. They were instructed to keep bleeding diary cards. Questions about hormone replacement therapy and experience of climacteric symptoms were also asked.
2.1. Climacteric status The women were assigned to three different categories with regard to climacteric status. The presence of mainly regular periods was defined as premenopausal status. Irregular bleeding or absence of bleeding for less than 12 months was classified as perimenopausal, and absence of bleeding for more than 12 months as postmenopausal. Women using hormone replacement therapy (HRT) constituted a separate group. During the study, HRT was prescribed to women who requested it. Some women had obtained a prescription from other doctors.
B. Larson et al. / Maturitas 28 (1997) 99–105
2.2. Hormonal analyses Circulating levels of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone and prolactin in serum were measured by radioimmunoassay methods using commercial kits (Diagnostic Products Corporation, LA).
2.3. Statistical methods Differences in distributions between groups were tested with the x 2 statistic and between means with the student’s t-statistic. Correlation analysis was carried out with Pearson’s product moment correlation. Survival analysis was applied to menopause status data, where time to menopause was treated in the same way as time to death in ordinary survival analysis. The log rank test was used to test differences between groups The study was approved by the Ethics Committee of the Karolinska hospital.
3. Results Out of 161 women invited, 151 (94%) came to the first visit. Four women dropped out during the study. All four visits were attended by 147 (91%) women. A total of nine women had reached menopause during the period from recruitment to the first visit and ten women had started HRT. During the 4 years of observation, nine women underwent hysterectomy and bilateral salpingooophorectomy, four because of myomas, three endometrial cancer, one ovarian cancer and one endometriosis. These women were excluded from further analyses.
3.1. Background In Table 1 and Table 2 background data are given. The majority of the women were married. The educational level of the women reflects that of the original population of 1399 women. Seventy three percent worked full time and 27% part time, the majority being employed in intermediary level jobs; 26% had professional jobs, 10% were
101
Table 1 Some sociodemographic characteristics Sociodemographic characteristics
Number (n)
Marital status Single 7 Married 115 Divorced 22 Widow 3 Education Primary 44 Secondary 54 College 49 Employment Full-time 107 Part-time 40 Occupation Higher professionals 15 Lower professionals 38 Service or clerical jobs 81 Unskilled jobs 12 House-wife 1 Smokers 33
Percentage (%)
5 78 15 2 30 37 33 73 27 10 26 55 8 1 22
executives or managers, 8% were employed in unskilled jobs and 1% were housewives. Ninety percent of the women had children; 47% had two children, which corresponds to the Swedish national average number [13], 10% were childless. Previous fertility problems were experienced by 16%. Questions concerning contraception were only asked when the women were 49 years old. A considerable percentage (61%) reported the use of some form of contraception. Table 2 Reproductive characteristics Reproductive characteristics Number of children 0 1 2 3 \4 Infertility Miscarriage/abortion Contraceptive users BMI*
Number (n)
Percentage (%)
15 25 69 35 3 24 53 90 23.7 (96.7)
10 17 47 24 2 16 36 61
* Expressed as [weight (kg)/height2 (m)]×100.
B. Larson et al. / Maturitas 28 (1997) 99–105
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Table 3 Distribution of menopausal status in relation to consecutive visits (V1 – V4)
Menopausal status Premenopausal Perimenopausal Postmenopausal HRT Hyst
V1 72 56 9 10 0
Visit V2 56 46 18 26 1
V3 8 58 17 58 6
V4 10 29 22 77 9
3.2. Transition to menopause The distribution of climacteric status over time is shown in Table 3. The number of premenopausal women decreased from 72 at first visit to ten at the fourth visit. The number of perimenopausal women was diminished from 56 to 29 during the study period and 22 women were postmenopausal at the fourth visit. Since two women reported irregular periods at visit 3, they were categorized as perimenopausal. At the fourth visit, they had regular periods and were classified as premenopausal. The number of women using HRT was 77 (53%) at visit 4. As could be expected, estradiol decreased significantly during transition to menopause and LH and FSH increased. There was no significant change in prolactin levels. FSH and LH levels at the first visit were strong predictors of menopause. Menstruating women with the highest levels of FSH and LH had their last menstruation significantly earlier than those with lower levels.
Table 4 Symptoms reported (%) at each visit
Vasomotor Vaginal dryness Urine incontinence Rate of stress incontinence
1
Visit 2
3
4
56 37 57 —
61 18 37 90
36 19 34 75
45 27 34 81
3.3. Symptoms The symptoms reported by the women at each visit are shown in Table 4. The consistency over time was greatest for urine incontinence which was reported by 57% at the first visit and 34% at visits 3 and 4, 15% of those moderate or severe. The correlation coefficient varied between 0.51 and 0.69 (PB 0.001) when measured between two adjacent occasions. No correlation between incontinence and hormone levels nor with other symptoms was found. On the other hand, incontinence was associated with parity and there was a trend of increasing prevalence with each child born (P(trend) = 0.02). The main difference was between nulliparous and parous women (P= 0.012). HRT did not have any effect on urinary symptoms. Vaginal dryness was reported by 37% at the first visit, only 6% having moderate to severe complaints. A total of 1/3 of the women were premenopausal. The symptoms did not correlate with hormone levels or the occurrence of vasomotor symptoms. When measured between two adjacent occasions, the correlation coefficients were 0.41– 0.50 (PB 0.001). Vasomotor symptoms varied most between visits with a correlation coefficient varying between 0.26 and 0.46 (PB 0.002). Hot flushes and sweating were significantly associated with high levels of FSH and LH (PB 0.001 and P=0.002, respectively) and with low levels of estradiol (P= 0.045). Women using HRT presented with the same rate of vasomotor symptoms as women not using HRT at the first two visits. At visits 3 and 4, however, women on HRT reported significantly less vasomotor symptoms than women without. The rate of vasomotor symptoms before and after initiation of HRT by time is shown in Fig. 1. At the first visit, while the women were still menstruating, the indication for HRT was predominantly vasomotor symptoms, which persisted at visit 2. At visits 2, 3 and 4 the proportion of women prescribed HRT due to vasomotor symptoms decreased in favour of other indications, such as prophylaxis for osteoporosis, vaginal dryness, sleeping disturbances and memory dysfunction. The positive effects of HRT increased at visits 2 and 3, but were slightly decreased at visit
B. Larson et al. / Maturitas 28 (1997) 99–105
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Fig. 1. Rate of vasomotor symptoms before and after initiation of HRT: (A) women prescribed HRT at first visit; (B) women prescribed HRT at second visit; (C) women prescribed HRT at third visit.
4, indicating a placebo effect. Only six women discontinued their therapy during the study. Cigarette smoking was not associated with hormonal levels nor with menopausal status or vasomotor symptom.
4. Discussion More than 50% of the women reported urinary incontinence at the first visit. It should be pointed out that this figure includes all types of incontinence. Moderate or severe incontinence was reported by 15%. The prevalence of urinary incontinence varies between studies, depending on age of the subjects and definition of the symptoms. The highest rates reported were 50 and 73% [14,15]. A prevalence peak of urinary incontinence around the menopause has been reported by Thomas et al. [16] and Jolleys [17]. In our study, urine leakage declined from 57% at the first visit to about 35% at the following three visits, due to a reduction of stress incontinence, in agreement with Holst and Wilson [18] and Reekers et al. [19]. An explanation might be that the women have received advice regarding pelvic muscle training
by the doctor in charge. No correlation between incontinence and hormonal levels nor with other symptoms or the use of HRT was found. This therefore suggests that menopause may not be crucial for the occurrence of these symptoms. On the other hand, incontinence was associated with parity. Thus, parity seems to be more important than climacteric-status for incontinence, which is in agreement with findings of Molander [4]. Vaginal dryness was reported by 35% of the women at the first visit, only 6% having moderate or severe complaints. No correlation to hormonal levels or to other symptoms was found. Vaginal dryness occurs most frequently 4–6 years after menopause [20] and is then related to low endogenous plasma levels of estrogens [21,22]. In our study, this symptom was at the first visit reported by 1/3 of the premenopausal women. The experience of vaginal dryness in our women is therefore probably not associated with vaginal atrophy of the epithelium due to estrogen deficiency, but can be explained by other factors such as relationship with partner. The frequency of vasomotor symptoms was about 60% at the first two visits and 1/3 of the premenausal women reported this symptom at
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each visit. The incidence of hot flushes in women around menopause is reported to be as high as 80% [23,24]. In a Swedish study [7], 44% of women aged 52–54 years reported moderate to severe vasomotor symptoms. It is also well known that a certain percentage of women experience hot flushes many years before menopause [9,25]. More than 1/2 of the women were using HRT at the last visit. The use of HRT in Sweden has increased 3-fold from 1990 – 1996 [26]. Furthermore, the indications for HRT have been expanded to include prophylaxis of osteoporosis which was accepted in 1992. It has been known that women who have regular contacts with medical practitioners are more likely to be using HRT [27]. In our study, the women saw a gynecologist annually, which could partly explain the high rate of HRT use, although women were only prescribed HRT on request. Today, there is an increasing tendency of women to start HRT while still menstruating. In a Danish study [28], 22% of the women 51 years of age used HRT, 42% of those had started during the premenopause; 40% discontinued HRT and reported no effect as reason for discontinuing. The mechanism behind hot flushes is not yet fully understood. Even if vasomotor symptoms are correlated to low estrogen levels in groups of women, neither estrogen deficit nor elevated gonadotropin levels have been linked to the initiation of a hot flush in the individual woman [29]. Thus, there is no rationale for treating hot flushes with estrogen in women who still menstruate and thus do not have low endogenous estrogen levels. This must be taken into consideration before prescribing HRT to premenopausal women. Acknowledgements We are grateful to Bo Nilsson for statistical calculations of the results of this study. References [1] Metcalf MG, Donald RA, Livesey JH. Pituitary-ovarian function in normal women during the menopausal transition. Clin Endocrinol 1981;14(3):245–55.
[2] Korenman SG, Sherman BM, Korenman JC. Reproductive hormone function: the perimenopausal period and beyond (review). Clin Endocrinol Metab 1978;7(3):625 – 43. [3] Burger HG. The endocrinology of the menopause (review). Maturitas 1996;23:129 – 36. [4] Molander U. Urinary incontinence and related urogenital symptoms in elderly women. Acta Obstet Gynecol Scand 1993;158:1 – 22. [5] Cardozo LD, Kelleher CJ. Sex hormones, the menopause and urinary problems. Gynecol Endocrinol 1995;9(1):75 – 84. [6] Dennerstein L, Smith AM, Morse C. Psychological wellbeing, mid-life and menopause. Maturitas 1994;20:1 – 11. [7] Hammar M, Berg G, Fa˚hreus L, Larsson-Cohn U. Climacteric symptoms in an unselected sample of Swedish women. Maturitas 1984;6:345 – 50. [8] Holte A, Mikkelsen A. The menopausal syndrome: a factor analytic replication. Maturitas 1991;13:193 – 203. [9] Hunter M. The South-East England longitudinal study of the climacteric and postmenopause. Maturitas 1992;14:117 – 26. [10] Kaufert PA, Gilbert P, Hassard T. Researching the symptoms of menopause: an exercise in methodology. Maturitas 1988;10:117 – 31. [11] McKinley SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14:103 – 15. [12] Collins A, Landgren BM. Reproductive health, use of estrogen and experience of symptoms in perimenopausal women: a population-based study. Maturitas 1995;20:101 – 11. [13] Statistiska Centralbyra˚n. Folk-och bostadsra¨kningen 1990. Stockholm, Sweden. (statistical information on the Swedish population). Swedish text. [14] Yarnell JWG, Voile GJ, Richards CJ, Stephensen TP. The prevalence and severity of urinary incontinence in women. J Epidemiol Community Health 1981;35:71 – 4. ˚ , Heimer G, Ulmsten U, Cnattingius S. Preva[15] Stenberg A lence of genitourinary and other climacteric symptoms in 61 year old women. Maturitas 1996;24:31 – 6. [16] Thomas TM, Plymat KR, Blannin J, Meade TW. Prevalence of urinary incontinence. Br Med J 1981;281:1243– 5. [17] Jolleys JV. Reported prevalence of urinary incontinence in women in a general practice. Br Med J 1988;296:1300– 2. [18] Holst K, Wilson PD. The prevalence of female urinary incontinence and reasons for not seeking treatment. New Zealand Med J 1988;101:756 – 8. [19] Rekers H, Drogendijk HA, Valkenburg RF. The menopause, urinary incontinence and other symptoms of the genito-urinary tract. Maturitas 1992;15:101 – 11. [20] Berg G, Gottgall T, Hammar M, Lindgren R. Climacteric symptoms among women aged 60 – 62 in Linko¨ping, Sweden, in 1986. Maturitas 1988;10:193 – 9. [21] Morse A, Hutton J, Jacobs H, Murray M, James V. Relation between the karyopycnotic index and plasma oestrogen concentration after the menopause. Br J Obstet Gynaecol 1979;86:981.
B. Larson et al. / Maturitas 28 (1997) 99–105 [22] Nilsson K, Heimer G. Endogenous estrogen levels in postmenopausal women with severe urogenital atrophy. Gynecol Obstet Invest 1992;34:234–6. [23] Ballinger SE. Psychosocial stress and symptoms of menopause; a comparative study of menopause clinic patients and non patients. Maturitas 1985;7:315–27. [24] Oldenhave A, Jaszmann LJB. The climacteric absence or presence of hot flushes and their relation to other complaints. In: Schonbaum E, editor. The Climacteric Hot Flush. Prog Basic Clin Pharmacol. Basel: Karger 1991;6:1 – 39. [25] Hagstad, A. Gynecology and sexuality of the mature woman. An epidemiological study. Doctoral thesis, University of Gothenburg, Sweden, 1985.
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