A longitudinal population study of climacteric symptoms and their treatment in a random sample of Swedish women.

OBJECTIVES: To assess, first, the prevalence and severity of symptoms associated with the climacteric period and their treatment and, second, the prevalence of exercise, smoking and body weight in a population-based sample of Swedish women. MATERIAL AND METHODS: Prospective, longitudinal cohort study, initiated in 1992, in women aged 46, 50, 54, 58 and 62 years with a follow-up 6 years later. Information was obtained from the same women (n=3816) on both occasions using a postal questionnaire regarding sociodemographic variables, general and reproductive health, the occurrence of climacteric symptoms and their severity, and the use of hormone replacement therapy (HRT). RESULTS: The prevalences of climacteric symptoms were as follows (1992/1998): vasomotor symptoms, 52%/62%; depression/irritability, 57%/65%; sleeping disturbances, 51%/69%; muscle/joint pain, 55%/70%; and loss of libido, 38%/57%. HRT with medium-potency estrogens was currently being used by 34% (1992: 14%), and 12% (1992: 8%) were using low-potency estrogens. The maximum prevalence of HRT (medium-potency estrogens) use was found in the 56-year-old group, at 46% (1992: 25% in the 54-year-old group). Body mass for the whole group had increased from 66.3 to 68.9 kg. Exercise was more frequent in all age groups in 1998 compared to 1992. There was a decrease in current smokers from 32 to 26% between the two periods. Compared with 1992, the women in all five birth cohorts considered themselves to be less healthy and quality of life had decreased for the whole group. CONCLUSIONS: The prevalence of symptoms associated with the climacteric period and the use of HRT had increased markedly in this longitudinal study of the same women followed between 1992 and 1998. During the same period, smoking decreased, while body weight and exercise frequency increased.

Factors associated with climacteric symptoms and the use of hormone replacement therapy.

BACKGROUND: To investigate factors associated with climacteric symptoms and the use of hormone replacement therapy (HRT). METHODS: A random sample of women aged 46, 50, 54, 58 and 62 years resident in Goteborg, Sweden (n=5,990) were invited by letter to complete a postal questionnaire concerning the menopause and HRT use. RESULTS: The response rate was 76% (n=4,504). Women with a higher education, who exercised regularly and who had regular spare-time activities felt better and had fewer climacteric complaints (p<0.001) compared to lower educated women, women who exercised infrequently and women who had no spare-time activities. Climacteric symptoms were associated with dryness symptoms (dry eyes, skin, hair and mouth), bilateral salpingo-oophorectomy (SOE), use of psychotropical drugs and use of alternative remedies, previous hysterectomy and full-time occupation. Stepwise multiple regression analysis showed significant correlations between vasomotor symptoms and various dryness symptoms, no menstrual periods and use of alternative remedies. Current HRT-users (13%) had used estrogens for 4.0 years and past users (14%) for 4.3 years. A correlation (p<0.005) was found between HRT use and previous use of contraceptive pills, use of alternative remedies and hysterectomy. Education, occupation and the frequency of exercise did not influence the prevalence of HRT use. CONCLUSIONS: This study has shown that the experience of climacteric symptoms and well-being is associated with many different factors. Women with a higher education and those who exercised regularly were more often symptom-free. HRT use was associated with previous use of contraceptive pills, use of alternative remedies and hysterectomy.

Bioavailability of norethisterone acetate alone and in combination with estradiol administered in single or multiple oral doses to postmenopausal women.

OBJECTIVES: Twenty-four postmenopausal women were randomly allocated to a cross-over trial for an investigation of the pharmacokinetics of norethisterone acetate (NETA; 0.5 mg), administered alone or in combination with estradiol (E2; 1 mg), both after a single oral dose. In a second trial, the above combination of 0.5 mg NETA with 1 mg E2 was administered daily for 28 days. METHODS: Plasma levels of NET, E2, estrone (E1) and estrone sulphate fraction containing an admixture of estrone glucuronide (E1S/E1G) were measured by radioimmunoassay at various intervals up to 72 h in the first trial and at the same intervals after the 28th day in the second trial. RESULTS: In the first, single-dose trial, pharmacokinetic parameters of NET were similar for NETA administered alone and its combination with E2. There was no statistically significant difference in the area under curve values AUC0-24 and AUC0-infinity and no apparent major differences were observed for other pharmacokinetic parameters. No carry-over effects due to the cross-over design were seen. The multiple dosage in the second trial did not cause any major changes in the pharmacokinetic parameters of NET, except for the AUC0-24 and AUC0-infinity values which were significantly higher than those seen in the first trial. The levels of E2 exhibited, shortly after the intake of E2, a rapid burst. The levels gradually decreased to a nadir followed by an increase to the main peak and by the subsequent elimination phase. The difference between the peak and nadir levels was significant (P < 0.05) in the second, multiple-dose trial. This bimodal pattern was not observed in earlier studies. The main metabolite of E2 was E1S/E1G, followed by E1, as could be seen from the AUC0-infinity values. These were, in both trials, approximately 300 and 7-times higher for the E1S/E1G and E1, respectively, than those for E2. For all analytes, the AUC0-24 values were significantly higher in the second trial than those found in the first trial, indicating accumulation upon repeated administration. Pharmacokinetics of all analytes remained linear in the second trial, as follows from the statistically established equality of AUC0-24 found in the second, multiple-dose trial with AUC0-infinity in the first, single-dose trial. The absorption half-life and t-max values of E1S/E1G appeared to be considerably shorter than those of E1 in both trials. CONCLUSIONS: The bioavailability of NET was not influenced by its combination with 1 mg E2. The most abundant metabolite of E2 was the E1S/E1G fraction, which may have served as the main source of E2 and other estrogens due to metabolic interconversions during the absorption and elimination phases.

Womens attitudes and knowledge about the climacteric period and its treatment. A Swedish population-based study.

OBJECTIVES: The aim of the study was to investigate womens knowledge and attitudes about the menopause and hormone replacement therapy (HRT). MATERIAL AND METHODS: Women aged 46, 50, 54, 58 and 62 years, born on uneven days, resident in Göteborg, Sweden (n = 5.990) were invited by letter to complete a questionnaire concerning the menopause and HRT. RESULTS: The response rate was 76% (n = 4504). Current estrogen use was reported by 21%. Another 20% had stopped estrogen use e.g. because of a fear of cancer (9%) or other side-effects (14%). The most common reasons to refrain from HRT were minor climacteric symptoms (27%), fear of cancer (9%) or side-effects (15%) and the opinion that the menopause is a natural process (20%). A majority (67%) preferred HRT without withdrawal bleedings, especially elderly women (80%). Thirty-five per cent could accept life-long HRT if treatment was free from withdrawal bleedings. Almost 70% received their information about the menopause and HRT from a physician. Forty-five percent of the women considered the menopause to be a relief. Approximately 60% had a regular sex-life. The most common reasons for not having a regular sex-life were irrespective of the womans age, the absence of a partner (43%). Loss of sexual desire (29%) or partners loss of desire (12%), both of which showed an increase with age, were other reasons given. Only 8% of the total population had no sexual activity because of vaginal dryness but in the oldest cohort (62 years old) 32% gave this as a reason. CONCLUSION: Physicians require more time for counselling of patients about the menopause and HRT. Many women refrain from therapy because of fear and misconceptions. To achieve better long-term compliance especially in elderly women the use of 'non-bleeding' regimes requires further attention.

The prevalence and severity of climacteric symptoms and the use of different treatment regimens in a Swedish population.

OBJECTIVES: To determine (i) the prevalence and severity of climacteric symptoms, and (ii) the prevalence of treatment for climacteric complaints, in a population based, random sample of Swedish women aged 46-62 years. MATERIAL AND METHODS: A random sample of 5990 women from the birth cohorts 1946, 1942, 1938, 1934 and 1930, resident in the city of Göteborg, was obtained from the population register. The women were invited by letter to complete a questionnaire concerning general health, reproductive history, climacteric symptoms (severity graded on a scale 0,1,2,3) and the treatment of climacteric complaints. The overall response rate was 76%. RESULTS: The prevalence of climacteric symptoms was as follows: vasomotor symptoms 53%, depression/irritability 57%, sleeping disturbance 52%, muscle/joint pain 57%, loss of libido 37% and vaginal dryness 21%. Hormone replacement therapy (HRT) with medium potency estrogens was currently being used by 13.4% and 7.7% were using low potency estrogens. Medium potency estrogens had previously been used by 14% and 6% had used low potency estrogens. HRT was reported to be effective against the most common climacteric complaints in 70%-90%. Non-hormonal treatment regimens had been used by 45% of the women and 31-63% reported a positive effect on climacteric symptoms. CONCLUSIONS: Although the majority of peri- and postmenopausal women reported suffering from climacteric complaints only 21% were current users of estrogens. Non-hormonal treatment modalities had been used by 45% of the women and were reported to have a good effect on climacteric symptoms in 45% compared to up to 90% of the HRT users.

Intrauterine administration of levonorgestrel 5 and 10 microg/24 hours in perimenopausal hormone replacement therapy. A randomized clinical study during one year.

OBJECTIVE: To investigate the clinical effects especially with regard to histopathology and bleeding patterns by levonorgestrel (5- or 10 microg/24 h) released from an intrauterine system (IUS) in combination with estradiol valerate (2 mg) given daily or transdermal estradiol (50 microg/24 h) in perimenopausal women. DESIGN: A prospective randomized single blind comparison during twelve months. SUBJECTS: One hundred and twelve perimenopausal women with vaso-motor symptoms. OUTCOME MEASURES: Histopathological assessment of the endometrium, ultrasonographic measurement of endometrial thickness, bleeding patterns, and acceptability. RESULTS: A total of 108 women started the study and 12 discontinued. The most common reason for discontinuation was frequent bleeding (six women). Thus, 96 (89%) women were followed for twelve months. In both the 5- and 10 microg levonorgestrel IUS groups the endometrium in all women but one was non-proliferative after twelve months and no case of hyperplasia was found. Irregular bleeding was reported during the first months of treatment but decreased after six months. At the end of the study 62% in the 5 microg- and 61% in the 10 microg group were amenorrhoic. The effects on bleeding patterns did not differ between the two levonorgestrel dosages. CONCLUSION: Continuous combined HRT was well accepted in perimenopausal women when the progestogen was given in an IUS. IUS's releasing 5- or 10 microg/24 h levonorgestrel seemed to minimize the progestogenic side effects and proved to be sufficient for effective prevention of endometrial stimulation by estrogen treatment in HRT in perimenopausal women.

Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteins.

Secretory nonpancreatic type II phospholipase A2 (snpPLA2) hydrolyzes fatty acids at the sn-2 position in phospholipids releasing free fatty acids (FFAs) and lysophospholipids. These products may act as intracellular second messengers or can be further metabolized into proinflammatory lipid mediators. The presence of snpPLA2 in extracellular fluids and serum during inflammation has suggested a role of the enzyme in this process. However, the presence of snpPLA2 in a variety of normal tissues suggests that snpPLA2 may also have physiological functions. Atherosclerosis appears to have an inflammatory component. Here we report on the snpPLA2 localization in normal and atherosclerotic lesions and on the properties of the isolated enzyme. A strong snpPLA2 immunoreactivity was observed in the arterial media that was colocalized with alpha-actin-positive vascular smooth muscle cells (SMCs) in both normal and atherosclerotic vessels. In aortic atherosclerotic lesions, snpPLA2 was observed colocalized with CD68-positive macrophages and HHF-35-positive SMCs and extracellularly in the lipid core. snpPLA2 was isolated from human normal arteries and from aorta with lesions. The enzyme was isolated by acid extraction of normal arterial tissues followed by immunoaffinity chromatography. The purified snpPLA2 had an expected molecular weight of 14 kD by polyacrylamide gel electrophoresis and appeared as a single band in immunoblotting. The enzymatic activity was followed by measuring release of fatty acids from phospholipid liposomes or LDL as substrates. The enzymatic activity was inhibited with two specific inhibitors for human snpPLA2: (1) monoclonal antibody 187 and (2) LY311727, a synthetic selective inhibitor. The mRNA for snpPLA2 was detected with reverse transcriptase polymerase chain reaction. These results indicate that snpPLA2 is present in human arteries and that it is able to hydrolyze phospholipids in LDL. The results support the hypothesis that snpPLA2 can release proinflammatory lipids at places of LDL deposition in the arterial wall.

Intrauterine or oral administration of levonorgestrel in combination with estradiol to perimenopausal women--effects on lipid metabolism during 12 months of treatment.

OBJECTIVE: Limited data concerning serum lipids and lipoproteins are available on the effect of HRT in perimenopausal women, who commonly have marked bleeding disturbances and may have severe climacteric symptoms. Almost all previously published data have utilized a simplified form of lipoprotein analysis, which includes an estimation and not a determination of LDL cholesterol. To delineate the role of locally administered progestogen, perimenopausal women were studied for a year. PATIENTS AND METHODS: 40 perimenopausal women with climacteric complaints. The continuous release of low-dose levonorgestrel from an intrauterine device was used as progestogen co-medication to estradiol in a new type of continuous combined hormone replacement therapy. Women were randomized to either cyclical treatment with 2 mg of oral estradiol valerate in combination with 250 micrograms of levonorgestrel for the last ten days (Cyclo Progynova) or continuously with 2 mg estradiol valerate orally in combination with a 20 micrograms per 24 hour levonorgestrel releasing intrauterine device. RESULTS: Reduced HDL cholesterol was initially recorded in both treatment arms and disappeared after 1 year of treatment. Triglycerides were reduced in the orally treated group, but not in the device group. No changes in LDL cholesterol were noted. CONCLUSIONS: The findings suggest that continuous combined HRT with intrauterine release of 20 micrograms levonorgestrel per 24 hours in perimenopausal women is neutral as far as lipid metabolism is concerned, since no alterations compared with pretreatment values could be noted after 12 months of treatment. Less marked lipid changes were obtained in perimenopausal women as compared with data on postmenopausal women. Differences in methodology may partly account for this.

Management of hormone replacement therapy: the Swedish experience.

OBJECTIVE: To describe the experience of Swedish physicians in the management of hormone replacement therapy (HRT). METHODS: A postal questionnaire was sent to a sample of Swedish women aged between 46 and 62 years of age. The sample represented one woman in two from the birth cohorts 1946, 1942, 1938, 1934 and 1930. RESULTS: A total of 5990 women were sent the questionnaire and 4525 (76%) completed and returned it. Of this sample, 21% currently used HRT and a further 20% had used it in the past. A high proportion who continued using HRT derived benefit from it which was reflected in relief from vasomotor symptoms, irritability, insomnia, vaginal dryness and muscle and joint pain. Only 27% of those trying other, non-hormonal therapy considered that they had benefited from it. The major reasons for not taking HRT was fear of side-effects, a belief that the menopause should not be interfered with, and at the recommendation of their physician. The same reasons were given by those women starting HRT but discontinuing it later. CONCLUSIONS: The figure of 21% using HRT compares favourably with other Scandinavian countries. A high proportion of HRT is prescribed by gynaecologists reflecting that many GPs were unfamiliar with its use. When HRT is given by GPs, many favour the transdermal route. Compliance is a major problem and few women continue long enough to benefit fully. One way of minimizing this is to ensure that patients are fully informed and have any fears and misconceptions dealt with. Adverse and misleading information from the media may have to be countered. Individualization of therapy is important and should be tailored to particular age groups. Transdermal HRT may be more acceptable in some cases.

17 beta-estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy.

OBJECTIVES: To evaluate low doses of 17 beta-estradiol (E2) and norethisterone acetate (NETA) as continuous combined hormone replacement therapy (HRT) in their effects on vasomotor symptoms, bleeding episodes, endometrial histology and mastalgia. METHOD: Sixty postmenopausal women were randomly allocated to three treatment groups and were given 1 mg E2 and 0.25 mg NETA (A), 1 mg E2 and 0.5 mg NETA (B) and 2 mg E2 and 1.0 mg NETA (C) in daily doses. The treatment period was 1 year. RESULTS: A similar statistically significant reduction of climacteric symptoms (P < 0.05) was found in all groups. Bleedings, mainly as spottings, occurred most commonly during the first treatment months. Fewer bleeding episodes and a higher percentage of amenorrhea was noted in group B compared to the other groups but did not reach statistical significance. All endometrial biopsies showed atrophy. Women in group A and B had less severe mastalgia (P < 0.05) compared to group C, given higher doses of steroids. CONCLUSION: Postmenopausal women taking 1 mg of E2 plus 0.5 mg NETA as continuous combined HRT reported a marked reduction of climacteric complaints and good bleeding control. No endometrial proliferation was detected after 1 year of treatment. This type of therapy may be beneficial especially for elderly women, in whom bleeding may be annoying.

Intrauterine administration of levonorgestrel in two low doses in HRT. A randomized clinical trial during one year: effects on lipid and lipoprotein metabolism.

OBJECTIVE: To investigate the effects on lipid and lipoprotein metabolism of two doses (5- or 10 micrograms/24 h) of levonorgestrel released from an intrauterine device (IUD) in combination with orally administered estradiol (2 mg estradiol valerate) in perimenopausal women. DESIGN: A 1-year prospective randomized single blind clinical trial. SETTING: Department of Obstetrics and Gynaecology, Ostra Hospital, Göteborg, Sweden. SUBJECTS: Fifty-one perimenopausal women with climacteric symptoms. OUTCOME MEASURES: Cholesterol in serum and in lipoprotein fractions; high-density lipoprotein (HDL), low-density lipoprotein (LDL). Triglycerides in serum and in very low-density lipoprotein. RESULTS: In both treatment groups significant elevations in HDL-cholesterol of similar magnitude were observed after 1 month and these changes were maintained during the 12 month observation period. In both treatment groups an initial significant decrease of LDL-cholesterol was observed and the decrement was maintained after 12 months. Serum levels of cholesterol decreased significantly in both groups after 1 month and were maintained after 12 months in the levonorgestrel-IUD (LNG-IUD) 5 micrograms group. However, the initial reduction of serum cholesterol in the LNG-IUD 10 micrograms group did not differ from baseline after 12 months. Serum triglyceride levels fluctuated during the observation period. No significant changes occurred. CONCLUSION: Continuous combined HRT with intrauterine administration of levonorgestrel, 5- or 10 micrograms/24 h, in perimenopausal women was observed to increase HDL-cholesterol and to decrease LDL-cholesterol compared with pretreatment values. The low doses of levonorgestrel did not reverse the beneficial effects on lipid metabolism usually seen after estradiol administration.

Intrauterine release of levonorgestrel--a new way of adding progestogen in hormone replacement therapy.

Forty perimenopausal women with climacteric complaints were randomly allocated to one of two estrogen-progestogen regimens. One group was treated cyclically for 3-week periods with 2 mg of estradiol (E2) valerate; during the last 10 days 250 micrograms of levonorgestrel was added. Another group was given 2 mg of E2 valerate a day and had a 20-micrograms/24-hour levonorgestrel-releasing intrauterine device (IUD) inserted. The study period was 1 year. Climacteric symptoms, bleeding patterns, and endometrial histopathology were recorded during the study. Subjective symptoms were equally diminished in both groups. In the IUD group, bleeding disturbances were gradually reduced, and 15 of 18 women became amenorrheic after 12 months, compared with the group given cyclic treatment in which all women bled regularly. No endometrial proliferation was found in any woman after 12 months. Thus, intrauterine release of 20 micrograms of levonorgestrel per day, in combination with orally administered E2, prevented endometrial proliferation and reduced uterine bleeding. This new approach to continuous combined hormone replacement therapy may be a well-tolerated treatment alternative in perimenopausal women.