Increased blood cadmium levels were not associated with increased fracture risk but with increased total mortality in women: the Malmö Diet and Cancer Study.

This study aimed to investigate if high levels of blood cadmium at baseline were associated with increased fracture risk during follow-up in middle-aged women. No increased fracture risk was observed during follow-up, but women with higher levels of cadmium had an increased overall mortality. INTRODUCTION: Exposure to high levels of cadmium has been associated with an increased fracture risk. The aim was to investigate a perceived association between low levels of blood cadmium (B-Cd) at baseline and risk of first incident fracture. METHODS: From the population-based Malmö Diet and Cancer Study Cardiovascular cohort, 2920 middle-aged women with available background questionnaire and B-Cd measurements were included. Women were divided into quartiles (Q) according to their cadmium levels (Cd-Q1 <0.18 µg/L, Cd-Q2 0.18-0.28 µg/L, Cd-Q3 0.28-0.51 µg/L, and Cd-Q4 >0.51 µg/L). National registries were analysed for prospective risk of fractures or death. Associations between B-Cd and fracture risk were assessed by survival analysis (Cox regression analysis). RESULTS: In total, 998 first incident fractures occurred in women during a follow-up lasting 20.2 years (median) (12.5-21.2 years) (25th-75th percentile). Women in Cd-Q4 were more often current smokers than in Cd-Q1 78.4 vs. 3.3% (p < 0.001) and the number of cigarettes smoked per day correlated with B-Cd (r = 0.49; p < 0.001). The risk of fracture was not associated with baseline B-Cd in adjusted models. The hazard ratio (HR) Cd-Q4 vs. Cd-Q1 was 1.06 (95% confidence interval (CI) 0.89-1.27). In the multivariate Cox regression, independent variables for increased fracture risk were history of gastric ulcer and increasing age, whereas increasing body mass index (BMI) lowered fracture risk. Overall mortality was significantly higher for women with high B-Cd, HR 2.06 (95% CI 1.57-2.69). CONCLUSIONS: Higher blood levels of cadmium did not increase fracture risk in middle-aged women but reduced overall survival.

Optimal tolerability of ultra-low-dose continuous combined 17beta-estradiol and norethisterone acetate: laboratory and safety results.

OBJECTIVE: To evaluate the influence of two ultra-low doses of oral continuous combined hormone therapy and placebo on metabolic parameters, and to assess safety endpoints and overall tolerability in healthy postmenopausal women. DESIGN: In a subpopulation of the Clinical study on Hormone dose Optimisation In Climacteric symptoms Evaluation (CHOICE) trial, lipids and parameters of glucose metabolism and hemostasis were analyzed in Nordic women (n = 158) at baseline and after 12 and 24 weeks of treatment with 0.5 mg 17beta-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA or placebo. Adverse events occurring from the first trial-related activity, whether related or not related to the study medication, were recorded for the entire population (n = 575) of the trial. The seriousness, relationship to treatment and the reason for withdrawal were reported. RESULTS: Both ultra-low-dose combinations were neutral to changes in lipid and lipoprotein, hemostasis parameters and carbohydrate metabolism during the trial. The incidence of serious adverse events was only 1% in respective treatment groups. Adverse events were the reason for withdrawal in only 2% and 6% of women in the 0.5 mg E2 + 0.25 mg and 0.1 mg NETA groups, and in 8% in the placebo group. No weight gain or change in blood pressure was reported during the trial in any of the study groups. CONCLUSION: The treatments had neutral effects on metabolic parameters in the study population. Excellent tolerability of both ultra-low doses resulted in high completion rates.

Sociodemographic risk factors of metabolic syndrome in middle-aged women: results from a population-based study of Swedish women, The Women's Health in the Lund Area (WHILA) Study.

BACKGROUND: Metabolic syndrome (MS) is a common health problem in menopausal women. According to The Adult Treatment Panel (ATP) III, MS includes the combination of three or more of the following risk factors: abdominal obesity, glucose intolerance, high blood pressure, high serum triglycerides and low levels of high density lipoprotein cholesterol. OBJECTIVES: To assess the prevalence of the MS in middle-aged women, and the relationships of sociodemographic factors to the MS. METHODS: This analysis covers 10,766 women born between December 2, 1935 and December 1, 1945, living in the Lund area of Sweden by December 1, 1995. RESULTS: We found that 11.6% of women with a mean (+/-standard deviation) age of 56.9 +/- 3.06 years had MS. Women with MS were older and had higher scores for body weight, body mass index, waist/hip ratio, pulse rate, pulse pressure, serum triglycerides and total serum cholesterol (p < 0.001 for all) compared to the control group. More MS women were smokers, less often consumers of alcohol, and less qualified. In addition, they had low-intensity physical activity at leisure time (p < 0.001) and high-intensity physical activity at work (p = 0.009). Premenopausal women and those treated with hormones had less MS (p < 0.001). Education, physical activity at leisure time, moderate intensity of physical activity at work, alcohol intake and smoking had strong association with MS but work status, household status and dietary habits had no significant association with MS. CONCLUSIONS: Sociodemographic features may contribute to MS. Hence, prevention of MS should encompass sociodemographic features.

Symptoms in peri- and postmenopausal women in relation to testosterone concentrations: data from The Women's Health in the Lund Area (WHILA) study.

OBJECTIVES: The aim of this study was to investigate possible associations between androgen concentrations in perimenopausal women and symptoms that may be associated with low androgen concentrations in the blood. METHODS: All women born in the period 1935-1945 and living in a defined geographic area in Sweden (n = 10 766) were invited to a screening program that included physical and laboratory examinations and a questionnaire. Three groups were identified: premenopausal women, women on hormone replacement therapy (HRT) and postmenopausal women without HRT. Concentrations of testosterone, androstendione, sex hormone binding globulin and estradiol were measured. Waist-hip ratio, body mass index and free testosterone index (FTI) were calculated. RESULTS: A total of 6908 women participated. The women on HRT had lower testosterone and FTI and were less satisfied with mood and energy (p < 0.05). Women with hot flushes had higher testosterone and FTI and women reporting coldness had lower concentrations (p < 0.05). Sexual well-being was not correlated to testosterone or FTI (p > 0.05). CONCLUSIONS: Lower testosterone concentrations were associated with lower quality of life in perimenopausal women but not to sexual well-being. There must be factors other than decrements in sex hormones that contribute to the emergence of some perimenopausal symptoms.

A double blind cross-over study on the effects of ORG OD14 compared to estradiol valerate and placebo on the fatty acid composition of serum lecithin and cholesterol ester in oophorectomized women.

Twenty-two women, oophorectomized in connection with surgical treatment for cervical carcinoma in clinical stage IB or IIA, were given ORG OD14 [(7 alpha,17 alpha)17-hydroxy-7-methyl-19-norpregn-5-(10)20-yn-3-one; 2.5 mg/day], a placebo, and estradiol valerate (2 mg/day), six weeks each, in a double blind, cross-over study. ORG OD14 is a synthetic steroid for continuous treatment of climacteric symptoms which in traditional bioassays has been shown to have weak estrogenic and progestogenic as well as very weak androgenic-anabolic properties. The aim of this study was to evaluate its effects on serum lecithin as well as on the relative fatty acid composition of serum lecithin and serum cholesterol ester. In serum lecithin, OD14 induced an increase in palmitic acid and a decrease in stearic acid, effects typical of 17-C-alkylated steroids, compared to both placebo and estradiol valerate. Furthermore, there was an increase in linoleic acid and a decrease in both arachidonic and dihomo-gamma-linolenic acid after OD14 administration. This decrease is interpreted as an inhibitory action of the steroid on the mechanisms of elongation and desaturation of linoleic acid and is considered to be an androgenic influence. The relative decrease is further accentuated by the decrease in total serum lecithin induced by OD14. Since these fatty acids are the major precursors for prostaglandin synthesis, these findings might have relevance in that context.

Important factors for use of hormone replacement therapy: a population-based study of Swedish women. The Women's Health in Lund Area (WHILA) Study.

OBJECTIVE: The aim of this study was to delineate the use of hormone replacement therapy (HRT) among women who were born between December 2, 1935, and December 1, 1945, and living in the Lund area of southern Sweden and to analyze factors that contribute to the acceptance and continuation of HRT. METHODS: All women received a generic questionnaire pertaining to demographic background, lifestyle, health behavior, and climacteric symptoms and underwent a personal interview. An interim analysis was carried out on 3,900 women. We mailed a hormone questionnaire to the women who were using HRT (n = 1,875). This hormone questionnaire covered, for example, menopausal status, complaints, and alterations in and efficacy of HRT use, as well as the reasons for discontinuing HRT use. RESULTS: A total of 1,415 (76%) women answered the hormone questionnaire. Forty-eight percent were HRT ever users, and 32% were current users. Mean duration of HRT use was 47 months. The most common incentives for HRT use were alleviation of menopausal symptoms (72%) and prevention of bone loss (50%) and/or cardiovascular disease (31%). Forty-seven percent of HRT users reported that they had changed regimens at least once. HRT users had higher education, full-time work, and a higher consumption of alcohol but less consumption of cigarettes. They reported higher frequencies of climacteric symptoms, past histories of premenstrual syndrome, use of oral contraceptives, and hysterectomy. They also had a higher consumption of healthcare resources. A total of 177 women withdrew from therapy. The most common reasons for discontinuation of HRT were weight gain, anxiety of cancer, bleeding, breast tenderness, and emotional problems. Compared with current users, past users had less positive as well as fewer negative effects of HRT. Several variables contributed to compliance, including education, full-time work, regular exercise, low frequency of persistent climacteric symptoms, and alteration of regimens. CONCLUSION: Education, working conditions, lifestyle, interest in prevention, and severity of the climacteric symptoms are determinants for both acceptance of and compliance with HRT.

Metabolic effects of continuous estradiol-progestin therapy in postmenopausal women.

Sixty postmenopausal women with climacteric complaints were randomly allocated to four treatment groups. Without interruption, each patient was given one tablet daily containing 2 mg 17 beta-estradiol along with either norethisterone acetate 1 mg and 0.5 mg or megestrol acetate 5 mg and 2.5 mg. Blood samples were obtained before treatment and then after 1, 4, and 12 months of treatment. Serum was analyzed for cholesterol and triglycerides in serum and for cholesterol in the ultracentrifugally separated lipoprotein fractions of very low-density lipoproteins, low-density lipoproteins, and high-density lipoproteins. Significant reductions of serum cholesterol were found in all treatment groups except for that given 2.5 mg megestrol acetate. After 1 and 4 months of treatment, low-density lipoprotein cholesterol decreased 7-22%, whereas high-density lipoprotein cholesterol was reduced by 2-16% in the four groups. No significant differences could be demonstrated among the groups in low-density lipoprotein cholesterol or high-density lipoprotein cholesterol during treatment, as assessed by analysis of variance. Thus, cholesterol metabolism was equally influenced by both progestin types. Accordingly, the clinical efficacy and acceptance would decide the preparation to be advocated for women in need of hormone replacement therapy.

Lipid metabolism in women with polycystic ovary syndrome: possible implications for an increased risk of coronary heart disease.

This study reports values of serum lipids, lipoproteins, and the relative fatty acid composition of lecithin and cholesterol ester in 20 women with typical polycystic ovary syndrome (PCO). These values were compared with values of 22 regularly menstruating women without clinical evidence of androgen excess. Higher levels of triglycerides in serum (P less than 0.05) and very low-density lipoproteins (P less than 0.01) and lower concentrations of free cholesterol in low-density lipoproteins (P less than 0.05) were found in the PCO women. In serum lecithin the PCO patients had higher palmitic and lower stearic acid levels compared with those of the normal women. This finding was interpreted as a reduction of the excretory capacity of the liver in the PCO group. No correlations between lipids and sex hormones were found. Body weights and blood pressures were higher in the PCO group. The results indicate that PCO women could be at increased risk for coronary heart disease, because an increased serum triglyceride level, body weight, and blood pressure are considered to be risk factors of coronary heart disease.

Cardiovascular disease in postmenopausal women.

With many risk factors for cardiovascular disease, myocardial infarction in particular now being well defined, it becomes increasingly clear that a majority of these factors are not only age, but also gender specific. Confidential risk factors such as smoking, hypertension, diabetes mellitus, overweight and hyperlipaemia, might have a different impact in women than in men. Moreover, there are substantial clinical differences between male and female ischaemic heart disease, both as to presentation, as well as to diagnosis, therapy and prognosis. In addition to a discussion to the risk factors mentioned above, the cardioprotective actions of oestrogens will be reviewed.

Quality of life in endometrial cancer survivors.

OBJECTIVE: The aim of this study was to evaluate the health-related quality of life in survivors of endometrial cancer (EC); and to identify common problems that they may encounter, in the hope of paving the way to improving their quality of life. STUDY DESIGN: We investigated and compared the health conditions and quality of life between EC survivors and the general population as a control group. There were 61 EC patients who were at clinical stage I-III and survived for 5-7 years after the primary treatments. The control group was composed of 527 healthy postmenopausal women. All of them completed a self-evaluated questionnaire pertaining to personal conditions, medical surveillance, individual well-being and quality of life. RESULTS: The EC survivors were divided into two groups: an older group (n = 34) and a younger group (n = 27). The latter was compared with the controls. In general, most of the EC survivors were old, low-educated women. The majority of them were in a poor condition. They were inactive, received medical surveillance and had regular medication. The distribution of various complications was higher in the older EC group while the climacteric symptoms were more common in the younger EC group. In both EC groups, the quality of life was lower than in the controls. The prevalence of somatic symptoms was higher in the older EC survivors and psychological problems were a common complaint of the younger EC survivors. CONCLUSION: The quality of life was poor in the EC survivors. To improve their life quality, earlier psychological counseling should be offered to EC survivors, in particular to younger and single women, and hormone replacement therapy (HRT) should be recommended, but on a selective basis, to those patients at low risk of cancer recurrence.

Quality of life in long-term survivors of cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the quality of life within a sample of cervical cancer survivors. STUDY DESIGN: In this study, 46 cervical cancer survivors at clinical stage I or II and one survivor at stage 0, were evaluated. Two control groups were selected from an ongoing cohort study, in which 527 women were postmenopausal and 344 women were postmenopausal with HRT. All controls and cancer survivors completed a self-evaluating questionnaire pertaining to personal conditions, medical surveillance, individual well-being and quality of life. RESULTS: Eighteen cervical cancer survivors were ovaries preserved. A total of 28 survivors, who had an oophorectomy, were compared with the controls. Most of the cancer survivors had a good socio-economic background and an active lifestyle. Forty-two percent were currently under medical surveillance and used medication regularly. The ratio of HRT users was higher in the oophorectomy group (36% in both short- and long-term therapy). With regard to the quality of life, there were no remarkable differences between oophorectomy survivors and controls. Except that the psychological condition in the ovaries preserved group was worse, the rest of the findings concerning the quality of life derived from the ovaries preserved group were rather close to that of the oophorectomy group. CONCLUSION: The quality of life in long-term cervical cancer survivors is generally satisfactory. The positive results may be due to the higher ratio of HRT use, ovarian preservation, good education, working conditions, as well as an active lifestyle.

Occurrence, nature and treatment of urinary incontinence in a 70-year-old female population.

An intervention trial using oral oestriol to treat urinary incontinence was performed in a number of patients taken from a representative sample of 562 women aged 75 yr. The clinical series consisted of 34 patients who took part in a double-blind crossover study of the possible effects of oestriol, given in a single daily dose of 3 mg, and of a placebo over a period of 3 mth. The clinical examinations included bacteriological cultures and an assessment of the degree of atrophy of the surface membranes in the vagina. In most patients, oestriol was effective in reversing the atrophy. The clinical effect was excellent in urgency and mixed incontinence, but not in stress incontinence.

Apolipoprotein A1 levels in oophorectomized women treated with Org OD 14, oestradiol valerate and a placebo.

Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium. The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E2V) and a placebo. Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E2V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period. There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E2V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease. Long-term treatment with OD 14 might therefore be hazardous in this respect.

Lipid metabolic studies in oophorectomised women: effects on serum lipids and lipoproteins of three synthetic progestogens.

Norethisterone acetate, medroxyprogesterone acetate and levonorgestrel were administered to oophorectomised women to evaluate the effects they have on lipid metabolism. Blood samples were drawn after a 3 wk period without hormone therapy and after 3 wk on each progestogen. Serum and lipoprotein lipids were followed and an oral glucose tolerance test with blood glucose and plasma insulin determinations were performed. The nortestosterone derivatives, norethisterone acetate and levonorgestrel, decreased high density lipoprotein cholesterol as well as alpha-lipoproteincholesterol, while the 17-hydroxyprogesterone derivative medroxyprogesterone acetate did not. Norethisterone acetate and medroxyprogesterone acetate impaired glucose tolerance. A difference between nortestosterone derivatives and 17-hydroxyprogesterone derivatives having an effect on high density lipoproteins is suggested.

Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints.

Subjective complaints, endometrial histopathology, vaginal cytology and bleeding patterns were recorded in 26 patients treated with a continuous oestrogen-progestogen regimen for 12 mth. A marked reduction of hot flushes and sweats were noted and the evaluation of endometrial specimens revealed that the mucosae were mostly inactive-atrophic. The karyopyknotic index proved to be a poor indicator of oestrogenic activity. The number of recorded bleedings in the peri-menopausal women differed markedly from the post-menopausal women during treatment; they were very slight in the latter group. Even in those cases where bleeding occurred, the endometrial samples were found to be atrophic. Vaginal bleeding seemed to be an unreliable indicator of endometrial histopathology. The present combination of hormones used in a continuous regimen is a good alternative for post-menopausal women in need of hormonal therapy.

A study of European womens' experience of the problems of urogenital ageing and its management.

OBJECTIVES: A six country Pan-European study of aspects of urogenital ageing (UGA). METHODS: The study was carried out using a stratified random sample of 3000 women between the ages of 55 and 75 years. RESULTS: A total of 30% suffered from UGA symptoms, of whom 60% made efforts to alleviate their UGA problems, most commonly using HRT. There were some international differences regarding womens' perceptions of HRT, sexual relationships, prevalence and treatment of UGA problems and their attitudes to them across the six European States. CONCLUSIONS: Despite some international differences there was a generally similar experience of UGA problems across the six European populations studied, with a minority of women suffering significantly, however the distress of that subgroup highlighted the need for health professionals to appreciate the impact of UGA on those affected and to understand that many of these older women may be reticent in seeking help.

Treatment of climacteric complaints with Org OD 14: a comparative study with oestradiol valerate and placebo.

Org OD 14 (7 alpha,17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) is a steroid possessing mixed hormonal activity, which in earlier studies has been shown to alleviate climacteric complaints and to prevent post-menopausal osteoporosis without affecting the endometrium. The effects of Org OD 14 on climacteric complaints were compared with those of oestradiol valerate (E2V) and placebo in a randomized, double-blind, cross-over study in 20 women who had been oophorectomized and hysterectomized 3-6 yr earlier as part of their treatment for cervical cancer. Each patient was treated orally for a total period of 18 wk, comprising 6 wk on each preparation. Capsules of identical appearance were given; these contained either 2.5 mg Org OD 14, 2 mg E2V or placebo. The patients' scores for symptoms and mood items on standardized rating scales were recorded at the end of each 6-wk treatment period (i.e. on days 43, 85 and 127). There were no differences between the effects of Org OD 14 and E2V on symptoms and mood items, while both compounds were more effective than placebo. Our findings confirmed that Org OD 14 is effective in ameliorating oestrogen deficiency symptoms in climacteric women.

A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy.

Previous studies have shown that continuous oral oestrogen-progestogen therapy, which is a relatively new treatment regimen, does not induce endometrial hyperstimulation. However, bleeding disturbances are common during the early months of therapy and in the present study we used both conventional methods of statistical analysis and a stochastic model to describe the bleeding patterns. Four groups of 15 post-menopausal women were given different oral formulations continuously for 1 yr. The oestrogen component in all cases was 2 mg 17 beta-estradiol. The progestogen used was norethisterone acetate at a dose of either 1 mg or 0.5 mg (Groups A and B) or megestrol acetate at a dose of either 5 mg and 2.5 mg (Groups C and D). Each woman kept a daily record of all bleeding episodes, 80% of which occurred during the first 4 mth of therapy. Analysis of variance showed that the high doses of the two progestogens were associated with less spotting and menstrual-like bleeding than the low doses. Stochastic analysis of the bleeding data confirmed that women on the high progestogen doses experienced fewer bleeding episodes than those on the low doses. It also showed that women receiving the high progestogen doses who weighed under 67 kg or had had their last menstruation over 5 yr previously bled less than the other women in the high-dose groups.

Effect of oestriol, oestradiol valerate and ethinyloestradiol on serum proteins in oestrogen-deficient women.

The effect of oestriol (3 mg for 3 mth), oestradiol valerate (2 mg for 3 mth) and ethinyloestradiol (0.025 mg for 21 days) on sex hormone binding globulin (SHBG), transcortin, ceruloplasmin and pregnancy-associated macro-globulin (PAG) was analysed in oestrogen-deficient women. The doses of oestrogens were therapeutically effective for the treatment of oestrogen-deficiency symptoms. Treatment with 0.025 mg ethinyloestradiol induced a 281% increase in PAG, a 119% increase in SHBG, a 74% increase in transcortin and a 74% increase in ceruloplasmin levels. Administration of 2 mg oestradiol valerate resulted in a 40% increase in SHBG, a small increase in transcortin and ceruloplasmin, whereas PAG levels remained unaffected. None of the parameters tested were affected by oestriol treatment. PAG was clearly the most sensitive parameter for ethinyloestradiol while SHBG was the most sensitive parameter for oestradiol valerate. These results show no relationship between clinical efficacy and effect of plasma protein synthesis, and demonstrate that one has to be very careful when comparing potency estimates for different oestrogens and different parameters.

Administration of dehydroepiandrosterone enanthate to oophorectomized women--effects on sex hormones and lipid metabolism.

Eight bilaterally oophorectomized women were given a depot injection of 200 mg DHEA-enanthate to study the effect on endocrine and lipid metabolism. A decrease in sex-hormone binding globulin (SHBG) and an increase in androstenedione was found 14 and 30 days after the injection. No changes could be detected in LH, FSH, oestrone, oestradiol or oestriol. Testosterone showed a tendency towards an increase. As compared to pre-treatment values, plasma lipids were unaltered after 30 days. A decrease in high density lipoproteins (HDL), cholesterol and in very low density lipoproteins (VLDL), free cholesterol, total cholesterol and phospholipids were seen in the lipid composition of the lipoproteins on day 30. These findings are in agreement with previous data reported after the administration of drugs with androgen-like effects. The relative fatty acid composition of plasma lecithin revealed only minor changes while the fatty acid composition of cholesterol esters indicated a decreased portion of essential fatty acids. These results suggest, in agreement with previous studies, an impaired endogenous cholesterol formation in the liver. The results from the analysis of the fatty acid composition of lecithin and cholesterol esters might indicate a decreased percentage of exogenous (dietary) cholesterol ester in plasma.