Early menopause: increased fracture risk at older age.

The aim of this study was primarily to determine the relationship between early menopause and the presence of fractures later in life, and secondly, to check for the significance of confounding factors (such as smoking habits, body mass index (BMI), weight and use of hormones). In this cross-sectional population based study, the subjects were 4725 postmenopausal women, 50-80 years of age, registered with 23 general practitioners (GPs). For the purpose of the present study, the total population was analyzed as well as the subgroup of 2757 women (the study population) with a natural menopause. Medical history questionnaire, weight, height and bone mineral density measurements were taken. Bivariate and multivariate analyses were carried out with documented fractures in three categories: during lifetime; after menopause and after age 50 years) as dependent variable and age, BMI, bone mineral density, weight, smoking habits, use of hormones and early menopause as independent variables. The total study population as well as the subgroups "early" and "normal menopause", stratified in three 10-year and in six 5-year categories, were analyzed. Results are expressed as odds ratio and 95% confidence intervals (CI). Multivariate logistic regression analysis revealed that over 70 years of age, BMD< or =0.800 ( t-score<2.5) and early menopause were the only systemic independent predictors of all three fracture categories. Comparing the subgroups normal menopause and early menopause, the early menopause group showed a statistically significant higher overall fracture rate (OR=1.5; CI 1.2-1.8). Over age 70, the difference in the prevalence of fractures reached statistical significance in each age category (OR: 1.8 and 2.1, respectively). Smoking was found to be associated with early menopause (OR=1.5; CI 1.2-1.8) but not with the presence of fractures. Height above 165 cm was found to be associated with a higher prevalence of fractures during lifetime. The present study shows that early menopause is statistically significant associated with the presence of fractures during lifetime, after age 50 years and after menopause. Especially at older age, early menopause is an important predictor of fractures.

Climacteric symptoms in a representative Dutch population sample as measured with the Greene Climacteric Scale.

OBJECTIVE: To measure climacteric symptoms in a population-based survey as assessed by the Greene Climacteric Scale and to obtain normative data for the total score and subscales (psychological, somatic, vasomotor, and sexual) of the Greene Climacteric Scale. METHODS: A sample representative of the Dutch female population is interviewed. The sample was drawn from the NIPO-Telepanel (with 269 women aged 45-65 years) and from the NIPO-CAPI@HOME database (a sample of 235 women aged 45-65 years). They all filled in the 21 items of the Greene Climacteric Scale. The women were divided in four groups according their menopausal status: premenopausal, perimenopausal, postmenopausal and posthysterectomy. RESULTS: The total score of the Greene Climacteric Scale (mean; SD) was in premenopausal women 10.53 +/- 7.36). The score in perimenopausal women (15.78 +/- 9.09) and postmenopausal women (15.33 +/- 9.01) were significant higher than in the premenopause. The same significant difference between pre and peri/postmenopausal women was observed in the psychological, somatic and vasomotor subscales. The depression subscale did not change significantly during the menopausal transition. Hysterectomized women had the same score as postmenopausal women, reflecting the rather high mean age of the hysterectomized women (55.8 years). CONCLUSIONS: Prevalence and intensity of climacteric symptoms as expressed in the Greene Climacteric Scale do increase during the menopausal transition and stay high during the postmenopause. Data presented can be considered normative for the Greene Climacteric Scale in a mainly Caucasian population.

Relationship of estradiol levels to breakthrough bleeding during continuous combined hormone replacement therapy.

OBJECTIVE: To determine whether serum estradiol and dydrogesterone concentrations are associated with the occurrence of breakthrough bleeding. METHODS: In a prospective, double-blind study, 194 postmenopausal women were allocated randomly to receive one of four doses of dydrogesterone (2.5 mg, 5 mg, 10 mg, 15 mg) continuously combined with 2 mg of micronized 17beta-estradiol. All medication was taken orally for a total of 168 days. Vaginal bleeding was recorded on a daily basis. Serum estradiol (E2) and dihydrodydrogesterone (the main metabolite of dydrogesterone) trough levels were measured at day 85 and at the end of the study (day 168). Bleeding pattern analysis was done according to the reference period method. RESULTS: One hundred fifty-two of 177 women who completed the study supplied valid data on drug compliance, smoking habits, bleeding episodes, and serum hormone concentrations, which were used to assess the impact of serum E2 and dihydrodydrogesterone concentrations on the occurrence of breakthrough bleeding. Logistic regression analysis identified only the serum E2 concentration as having an independent, statistically significant effect (P = .003) on the occurrence of breakthrough bleeding; no such effect was associated with dihydrodydrogesterone levels (P = .118). The relative risk for the occurrence of breakthrough bleeding was 2.7 (95% confidence interval [CI] 1.454, 5.609) for serum E2 concentrations greater than 40 pg/mL. CONCLUSION: The occurrence of breakthrough bleeding during continuous combined hormone replacement therapy with estradiol and dydrogesterone in postmenopausal women was related to serum estradiol levels and not to dydrogesterone levels. Further studies are needed to test the hypothesis that estrogen is a major factor in the incidence of bleeding during postmenopausal hormone replacement therapy.

Bleeding patterns and endometrial histology during administration of low-dose estradiol sequentially combined with dydrogesterone.

OBJECTIVE: To determine bleeding patterns and endometrial response in postmenopausal women taking low-dose (1 mg) estradiol in a sequential combined formulation with 5 or 10 mg dydrogesterone. METHODS: A total of 151 postmenopausal women were allocated randomly to 5 or 10 mg dydrogesterone during cycle days 15-28 in a sequential oral formulation with 1 mg estradiol continuously during 13 cycles of 28 days. Occurrence of vaginal bleeding was recorded daily and analyzed in accordance with World Health Organization (WHO) standards. Endometrial biopsies, obtained at baseline and cycle days 25-27 of the final treatment cycle, were interpreted independently by two pathologists. RESULTS: The study was completed by 131 women (87%). The percentage of women with bleeding (mean +/- SD) was 57.2 +/- 3.6% in the 1/5-mg group and 65.8 +/- 4.2% in the 1/10-mg group (p < 0.001); cross-sectional analysis showed that, in every cycle, there were more women with bleeding in the 1/10-than in the 1/5-mg group (p < 0.001). With regard to the day of onset of bleeding, the mean difference between groups was 1.4 +/- 1.1 days (p < 0.001). There was no difference in duration of bleed (5 days), or intensity or incidence of intermittent bleeding (3-14% per cycle). Both regimens resulted in high rates of amenorrhea in each cycle (26-49%), but only 14/151 (9%) women were amenorrheic throughout. Three patients (2%) discontinued owing to bleeding problems. Endometrial protection was adequate in 98.3% (1/5-mg group) and 98.5% (1/10-mg group) with only one case of proliferation (1/10-mg group) and one of simple hyperplasia (1/5-mg group). CONCLUSIONS: The bleeding pattern associated with low-dose (1 mg) estradiol sequentially combined with 5 or 10 mg dydrogesterone shows a high rate of amenorrhea in each cycle; there is a dydrogesterone dose effect on the occurrence and day of onset of bleeding. Bleeding episodes that occur show a regular pattern and are of slight intensity. The endometrial safety of both regimens is high.

Representative assessment of long bone shaft biomechanical properties: an optimized testing method.

Whole bone bending tests are commonly used in mechanical evaluation of long bones. Reliable information about the midshaft can only be obtained if the bending moment is uniformly distributed along the shaft, and if the distribution of the bending stress is not adversely influenced by rigid clamping of the bone ends. A testing device was developed to determine bending stiffness of long bones in 24 directions, perpendicular to the bone axis. For optimal distribution of bending moment and stress, four-point bending was performed, and bone ends were simply supported, not rigidly clamped. The method was validated by repeated testing of a stainless steel rod, and a sheep femur. Left-right ratios were assessed twice in 2 groups of 5 sheep: one control group, and one group in which the left femur was stabilized with a stainless steel interlocking nail for 2.5 yr, after a midshaft osteotomy. Test results obtained with the steel rod reproducibly were close to predicted values. Measurements with the sheep femurs were reproducible and precise for 3 of the 4 parameters of the bending test. Stiffness parameters were significantly higher in the operated sheep than in the control group. We conclude that the method described here provides accurate and reproducible information, which is representative for the long bone shaft.

Quantification of fracture healing with three-dimensional computed tomography.

Quantitative methods are necessary for an objective evaluation of fracture healing. Three-dimensional computed tomography (CT) for the measurement of callus volume and density could be such a method and was investigated in an animal model. In 23 goats a closed tibial fracture was created and stabilized with a cast. The animals were killed at 2, 4 and 6 weeks for radiographical, CT and biomechanical analysis. From the CT scans a three-dimensional reconstruction of the callus was made to measure its volume and mean density. At 2 weeks the callus volume had already reached its maximum. In contrast, callus density, torsional strength and torsional stiffness increased over time (P < 0.0001, analysis of variance, ANOVA). Multiple regression analysis showed that the callus volume was not related to the torsional properties. However, callus density was a significant explanatory variable for both torsional strength (R2 = 0.72, P < 0.0001) and torsional stiffness (R2 = 0.82, P < 0.0001). Therefore, callus density as measured by three-dimensional CT is a predictor of the extent of fracture consolidation. CT with three-dimensional reconstruction of the callus seems a valid technique for the quantification of fracture healing.

Duration of hormonal replacement therapy in general practice; a follow-up study.

OBJECTIVES: To assess the mean duration of use of HRT in general practice and to identify determinants of the duration of HRT use. METHODS: A general population of 1689 women aged 45-60 years and enlisted in five group practices of general practitioners were followed for 9 months to trace first HRT prescriptions. All 103 women who were prescribed HRT were followed for a period of 2.25 years. Duration of HRT was assessed by using the data provided on the dispensing of HRT. Possible determinants of duration of use, such as attitude towards menopause, menopausal status and another six variables were measured by means of a questionnaire. RESULTS: None of the 103 women received HRT for a preventive purpose; the main indication was menopausal complaints. More than 60% of the women stopped their HRT within 6 months and only 8% of the women remained on HRT for more than 2 years. The mean duration of use was 7 months. Determinants that significantly predicted the duration of HRT use were age, attitude towards treatment of the menopause and the group practice. CONCLUSIONS: The mean duration of HRT use is very short, despite the fact that the most prevalent indication is the alleviation of menopausal symptoms. Apparently, Dutch women are presently unwilling to take HRT for longer periods.

Women's expectations and acceptance of cyclic induced HRT bleeds.

OBJECTIVES: To assess women's expectations and acceptance of cyclic induced HRT bleeds before and after their participation in a 1-year study and to compare the impact of these cyclic bleeds with that of previous menstrual bleeds. METHODS: A structured bleeding questionnaire was used to gather information: at baseline (before screening) on previous menstrual cycle patterns and accompanying discomfort, oral contraceptive use, current smoking habits, parity and the acceptance, preferences and expectations regarding HRT-induced bleeds. Women with amenorrhoea of 6 months or more and FSH levels (35 IU/l then received a daily oral dose of 1 mg 17 beta-oestradiol on days 1-28, combined with either 5 or 10 mg dydrogesterone on days 15-28, for 12 months (13 cycles of 28 days). At the end of their participation, women were again interviewed about their actual experiences with HRT-induced bleeds. RESULTS: One hundred and fifty-four women completed the questionnaire at baseline and 141 (including 131 completers) responded at the end. At baseline, 82% indicated to be pleased that menstruation had ceased, but nevertheless 94% stated that return of periods would be acceptable. At the end, 91% still found the occurrence of cyclic bleeds acceptable; this mostly depended on the perceived benefits outweighing the discomfort. Of the women who actually experienced bleeds (101) 60% regarded discomfort and blood loss less than during their previous menstrual cycles. A regular cycle pattern was considered more important than modest flow and short duration. CONCLUSIONS: In contrast to other studies, the acceptance of renewed vaginal bleeds in our study was high.

Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy.

OBJECTIVES: To determine if the efficacy of continuous low dose estradiol released from a vaginal ring is equivalent to estriol vaginal cream regarding improvement of the patient's subjective feeling of vaginal dryness and to determine if there is a preference for either of the two study treatments. METHODS: Open-label randomized parallel group trial with active control with a blind evaluation of vaginal cytology and with a cross-over (change-over) phase for preference comparison. One hundred and sixty five postmenopausal women with symptoms of vaginal dryness and signs of vaginal atrophy were randomized to an estradiol ring (Estring) or estriol cream (Synapause). The duration of each treatment period was 12 weeks. RESULTS: Both study treatments were equally effective regarding the ability to alleviate the symptom feeling of vaginal dryness and the signs of vaginal atrophy. Both treatments were efficient in restoring the vaginal mucosa, recorded as higher maturation values and as decreased vaginal pH. Estring was superior to estriol cream regarding preference of treatment. Both treatments were equivalent for the occurrence of adverse events, including bleeding. CONCLUSION: data from this change-over study confirm efficacy and safety of both the vaginal ring and cream in the treatment of postmenopausal women with urogenital atrophy symptoms and signs. The patients had a strong preference for the vaginal ring.

Vasomotor symptoms and well-being in the climacteric years.

OBJECTIVES: To determine more closely the relationship between vasomotor symptoms, well-being and climacteric status according to the last menstrual bleeding and according to the women themselves. METHODS: A population-based cross-sectional study was executed using a postal questionnaire. Well-being of women with and without vasomotor symptoms was compared, for the different menopausal statuses. All 2729 women living in a commuter suburb of Rotterdam aged 45-60 years were approached of whom 1947 (71.3%) responded. Well-being was measured by the Inventory of Subjective Health (ISH) and three subscales of the Sickness Impact Profile (SIP). RESULTS: The results showed that the relationship between vasomotor symptoms and well-being was dependent on climacteric status. Pre- and (middle and late) postmenopausal women with vasomotor symptoms more often experienced a relatively lower level of well-being compared to women without these symptoms. However, when the prevalence of vasomotor symptoms is as its peak, i.e. in late perimenopause, a difference in the level of well-being between women with and without vasomotor symptoms was absent. CONCLUSIONS: It is concluded that well-being and vasomotor symptoms were inversely related in all menopausal statuses except for the (late) perimenopausal phase. For this no somatic explanation seems plausible. A more social scientific explanation is suggested.

The climacteric in The Netherlands: a review of Dutch studies on epidemiology, attitudes and use of hormone replacement therapy.

The climacteric has been the subject of research in the Netherlands for several decades. The incidence of climacteric symptoms has not changed since the pioneerwork of Jaszmann in 1967; nevertheless the number of contacts with a physician decreased by a factor of three during the 1970s and early 1980s. A rise in the number of contacts has occurred since 1987-1988 and nowadays the same number is reached as was 20 years ago. In 1970 psychopharmacons were the first choice of therapy. Nowadays 90% of the prescriptions for climacteric complaints are hormones. Twelve percent of women aged 45-60 years are current users of HRT. The mean duration of HRT use is only 7 months. The positive attitude of most women towards the climacteric is an explanation for this very short duration of use. Women receive their information on HRT use mainly through women's magazines and TV programmes and not through physicians. The determinants of longer duration of use are a positive attitude to treatment, younger age and the support of the GP. Physicians claim that they prescribe progestogens for 51% of oestrogen users, but the data give a figure of only 20% of prescription of progestogens with oestrogens. One explanation for this difference is the practice of many doctors to prescribe progestogens only once in 3 months.

Determinants of first prescription of hormone replacement therapy. A follow-up study among 1689 women aged 45-60 years.

The aim of the present study was to ascertain the cumulative incidence of first hormone replacement therapy (HRT) and the factors that predict its prescription. In a general population 1689 women were followed for 9 months in order to trace first HRT prescriptions. Determinants (well-being, attitude towards menopause, menopausal status and another 9 variables) were measured by means of a questionnaire. Data analyses were performed for all women and for women with or without typical climacteric complaints. The cumulative 9 month incidence of HRT was 6.2%. For women without typical complaints a lower level of well-being (odds ratio 5.5; 95% CI 1.9-15.5) and the former use of the contraceptive pill (odds ratio 4.6%; 95% CI 1.0-20.5) were independently associated with HRT prescription. For women with typical complaints a positive attitude towards 'menopause should be treated' (odds ratio 3.8; 95% CI 1.8-8.0) was a determinant of HRT prescription. The cumulative incidence of HRT prescription is high, but from additional data it is apparent that within a period of 1 year and 9 months the majority of women stop taking HRT. For women without typical complaints, physicians prescribe HRT five times more often to those with a lower level of well-being. For women with typical complaints the physician's prescription is primarily related to the woman's attitude towards (medical) treatment of the menopause.

The view of women aged 45-65 and their partners on aspects of the climacteric phase of life.

OBJECTIVE: to make an inventory of the opinions and attitudes of the Dutch female population (aged 45-65) and their partners on the climacteric period. DESIGN: Data were collected as part of a weekly computer assisted questionnaire filled in by a representative panel composed of 234 women aged 45-65 and their partners. SETTING: A random sample of the population of The Netherlands. RESULTS: 12% of the women were current users of hormone replacement therapy (HRT), 21% had been hysterectomized, 32% were smokers. Although the prevalence of climacteric symptoms was as expected, only 1 out of 3 peri- and post-menopausal women were really troubled by the symptoms and had consulted a physician. The attitude towards HRT was neutral. Most women preferred a natural approach as a solution to the problems. Information on the climacteric was mostly obtained via the media, but in general the self-assessed level of knowledge was regarded by the panel as very low, even in current HRT users. Women on HRT were more positive toward treatment, and less confident about the spontaneous disappearance of the problems. Nearly all women, including current HRT users, regarded the absence of menstruation as a relief. Partners of climacteric women had the same opinion as their wives on all items. CONCLUSION: There is a lack of information on the climacteric and on the use of HRT. The Dutch female population tends to a natural approach of the climacteric without medication, but the general attitude can be regarded as neutral.

Women's opinion on withdrawal bleeding with hormone replacement therapy.

The objective of the study was to assess the opinion of women about the use of hormone replacement therapy (HRT) in relation to continuation or re-induction of bleeding periods after menopause. The design was a population-based cross-sectional study using a postnatal questionnaire in Krimpen aan den IJssel, a commuter suburb of Rotterdam. The participants were all 2729 women living in Krimpen aan den IJssel aged 45-60 years, of whom 1947 (71.3%) responded. The main outcome measure was an opinion on monthly or trimonthly withdrawal bleedings with HRT. The results showed 16.9% of all women have no or little objection to use of HRT with monthly withdrawal bleedings. There is a marked difference between premenopausal women (32.4% have no or little objection) and postmenopausal women (only 9.2% have no or little objection). Trimonthly cycles during HRT tend to be perceived as more acceptable (41.4% of premenopausal women and 11.8% of postmenopausal women have no or little objection). It is concluded that a reasonable proportion of premenopausal women accept continuation of periodic bleeding with HRT. There is a preference for trimonthly cycles rather than monthly withdrawal bleedings. Most postmenopausal women object to having withdrawal bleedings with HRT, irrespective of a monthly or trimonthly cycle. Research should continue on schedules without withdrawal bleedings.

Relationships between attitude towards menopause, well-being and medical attention among women aged 45-60 years.

This study aims to answer the following questions: (i) what is the attitude of women in the climacteric years towards menopause, (ii) what is the association between attitude towards menopause and well-being and (iii) to what extent is medical attention determined by both well-being and attitude towards menopause. All 2729 women aged 45-60 years living in a suburb of Rotterdam were sent a questionnaire, of these 1947 (71.3%) were returned. Attitude was measured on a 5-point rating scale using 28 items that have been used in other studies. Well-being was measured by the Inventory of Subjective Health and three subscales of the Sickness Impact Profile. Medical attention was measured by asking the women whether they were currently being treated by a general practitioner or specialist. Results show that three clusters of attitudes towards menopause exist: two clusters encompasses items reflecting attitudes towards disadvantages and advantages of the menopause, one cluster encompasses items reflecting attitudes towards (medical) treatment of the menopause. On the whole, women answer neutrally to items relating menopause with the disadvantages and tend to agree with items relating menopause with the advantages. The women slightly agree, premenopausal women more than others, with items that are in favour of treatment of menopausal complaints. Agreement with items on the disadvantage cluster is moderately associated with a low level of well-being, whereas agreement with items on the advantage cluster is slightly associated with a high level of well-being; the treatment cluster is not associated with well-being. Both well-being and agreement with items on the treatment cluster are statistically significantly associated with medical attention. Apart from these variables, the woman's ideas about treatment are also related to medical attention.

The climacteric and well-being.

The climacteric is accompanied by many changes in life, which may give cause to a variety of complaints. Thus, it may be difficult to discern to what extent the climacteric is related to well-being. The association between menopausal status and well-being was determined in a population of 2729 women aged 45-60 years. A self-administered questionnaire was filled out and returned by 1947 women (response 71.3%). Well-being was measured by the Inventory of Subjective Health (ISH) and the three subscales of the Sickness Impact Profile (SIP): social functioning; emotions, feelings and sensations; and intellectual functioning. The relationship between menopausal status and well-being was estimated using linear regression analysis, while adjusting for age and other potential confounding variables, including body mass index, smoking behavior, education, work outside the home, parity, way of cohabitation, difference in age with the partner and partner's employment. The results show that early perimenopausal women report a lower level of well-being as compared to premenopausal women on all three SIP scales. Early postmenopausal women report a lower level of well-being on the SIP emotions, feelings and sensations. Intermediate postmenopausal women have a lower level of well-being on the ISH only. Finally, late postmenopausal women have a lower level of well-being on the SIP social functioning and SIP emotions, feelings and sensations. We tentatively conclude that the influence of the climacteric on well-being independent of confounders is primarily found in behavioral functioning in the daily life of a woman.

Bone mineral content of the forearm in healthy Dutch women.

Single energy photon absorptiometry is a reliable technique for assessing the bone mineral content (BMC) of cortical bone in the forearm. It can also be used for BMC measurement in the ultradistal part of the forearm, where there is a considerable proportion of trabecular bone. The results of a BMC survey at both sites in healthy Dutch women, aged 26-75 yr, are reported, and the differences and changes with age are discussed. The technique offers possibilities for a rational screening programme in post-menopausal women, because of its high precision, low radiation dose, speed and low cost. The validity of the ultradistal measurement for the detection of abnormally fast bone mineral loss from trabecular bone in the individual patient has yet to be proven.