[Methods and results of in-vitro fertilisation in the Netherlands in the years 1983-1994]. / Methoden en resultaten van in-vitrofertilisatie in Nederland in de jaren 1983-1994.

OBJECTIVE: To describe methods and results of in-vitro fertilisation (IVF) treatment during the first 12 years after the introduction of IVF treatment in the Netherlands. Design. Retrospective cohort study. METHOD: A nationwide study was conducted among women who had had their first IVF cycle stimulated with gonadotrophins in 12 IVF centres in the Netherlands in the period 1 January 1983 to 31 December 1994 (n = 8, 184). RESULTS: The subfertility diagnosis related to tubal factors decreased from 70% in 1987 to 25% in 1994. The subfertility diagnosis related to a male factor increased from 8.7% in 1987 to 35.5% in 1994. The mean age at first IVF treatment remained roughly constant. During the introduction of GnRH agonists there was an increase in gonadotrophin dosages, the number of retrieved oocytes, the number of high responders and/or women who experienced an ovarian hyperstimulation syndrome (OHSS). The percentage of deliveries with at least one baby born alive after the first IVF cycle increased from 6% in 1984 to 18% in 1994. The number of live births per 100 transferred embryos increased from 2.5 in 1985 to 12 in 1994. Furthermore, the mean numbers of embryos transferred after the first IVF cycle decreased from 3.2 in 1987 to 2.2 in 1994. The overall success rate - defined as the proportion of women who had at least one child born alive after one or more IVF cycles - for women who had their first IVF treatment between 1983 and 1994 was 37.1%. The percentage of triplets or quadruplets decreased from 8.7 in 1989 to 1.2 in 1994. The percentage of twin deliveries remained about 25. CONCLUSION: The introduction of GnRH agonists and the higher dosages of gonadotrophins led to a higher oocyte harvest. During the first years of IVF treatment there was an increase in the success rate after the first treatment cycle. The overall success rate remained constant after 1991. The risk of developing an OHSS increased whereas the rate of twin deliveries remained constant.

Increase in breast size after menopause: prevalence and determinants.

OBJECTIVES: To determine the prevalence and determinants of increases in breast size after menopause. METHODS: Subjects were 1130 postmenopausal women, aged 54-71, participating in a population based breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Questionnaire data on changes in breast size, parity, age at first childbirth, breast feeding, age at menarche, age at menopause, HRT use and usual weight between age 30 years and age at questionnaire were used. Weight and height were measured at three screening rounds and waist and hip circumference was measured once. RESULTS: 18.6% of the women reported that they had to buy a larger bra because of changes in breast size, whereas 1.7% reported that they had to buy a smaller bra. Weight gain, waist circumference, hip circumference, Quetelet's index at third screening, Quetelet's index at first screening, waist-to-hip ratio and years since menopause were significantly associated with increased breast size (odds ratios between 2.5 and 1.4) (all tests for trend P < 0.05), whereas age at menopause, HRT use, parity and age at menarche were modestly, though not significantly associated with increased breast size. Age, usual Quetelet's index, age at first childbirth and number of months of full breast feeding were not associated with increased breast size. CONCLUSION: About one in five women experienced an increase in breast size after menopause. The most important factor associated with such an increase was found to be weight gain.

Oral contraceptive use in relation to age at menopause in the DOM cohort.

BACKGROUND: We investigated the hypothesis that long-term use of oral contraceptives (OCs), in particular high-dose OCs, could postpone age at menopause. METHODS: Data was used from 8701 women who participated in a breast cancer screening programme in Utrecht (DOM-3 cohort), and who did not use hormone replacement therapy (HRT) or OCs in the 4 years prior to their last menses. Data on OC-use, menopausal status, age at menopause, year of birth, parity, smoking behaviour, socio-economic status, body mass index and age at menarche was available. Use of high-dose OCs has been defined in this study as OC-use before 1972. The data was analysed by means of linear regression and Cox's proportional hazards analysis. Women still menstruating, women with surgical menopause and women lost to follow-up were censored at their last known date of menstruation. Endpoint was the natural menopause (n = 4589). RESULTS: The use of high-dose OCs advanced the onset of menopause by approximately 1.2 months for every year of OC-use compared with no OC-use. High-dose OC-use for > or = 3 years, adjusted for confounding variables, increased the risk of earlier menopause compared with no OC-use (adjusted hazard ratio 1.12; 95% CI 1.03--1.21). The use of lower dose OCs did not increase the risk of earlier menopause (adjusted hazard ratio 1.00; 95% CI 0.91--1.09). CONCLUSIONS: These results are inconsistent with the hypothesis that long-term use of OCs could postpone the onset of menopause by inhibiting follicle depletion. Possible explanations are discussed.

Urinary phytoestrogens and postmenopausal breast cancer risk.

Phytoestrogens are defined as plant substances that are structurally or functionally similar to estradiol. We report the associations of two major phytoestrogens, genistein and enterolactone, with breast cancer risk, using urinary specimens collected 1-9 years before breast cancer was diagnosed. The subjects were 88 breast cancer cases and 268 controls, selected from a cohort of postmenopausal women (n = 14,697) who participated in a breast cancer screening program. Mean levels of urinary genistein and enterolactone were determined by time resolved fluoroimmunoassay, using an average of two overnight urinary samples obtained from each participant on the first and the second screening rounds with a time interval of approximately 1 year. Odds ratios (ORs) of the highest to the lowest tertile of urinary phytoestrogen/creatinine concentrations and 95% confidence intervals (CIs) were computed. Higher urinary genistein excretion was weakly and nonsignificantly associated with a reduced breast cancer risk. OR for the highest tertile compared with lowest tertile was 0.83; 95% CI, 0.46-1.51. Higher urinary enterolactone excretion was weakly and nonsignificantly associated with an increased breast cancer risk. OR for the highest tertile compared with the lowest tertile was 1.43; 95% CI, 0.79-2.59. Tests for trends for both phytoestrogens were nonsignificant. We were not able to detect the previously reported protective effects of genistein and enterolactone on breast cancer risk in our postmenopausal population of Dutch women. Such an effect may be smaller than expected and/or limited to specific subgroups of the population.

Determinants of long-term hormone replacement therapy and reasons for early discontinuation.

OBJECTIVE: To identify factors associated with long-term hormone replacement therapy (HRT) and reasons for early discontinuation of it. METHODS: A cross-sectional study was conducted in four United Kingdom group general practices. Six hundred fifteen past or present HRT users (representing a response rate of 66%) responded to questionnaires on HRT and potential determinants of long-term use. Main outcome measures were long-term HRT use (at least 6 years) as opposed to short-term use (at most 2 years) and self-reported reasons for discontinuation. Odds ratios (ORs) of long-term use were adjusted for age and other variables, in the same groups, calculated by logistic regression and 95% confidence intervals (CIs). RESULTS: Ovariectomy (OR 2.59, 95% CI 1.12, 5.97), hysterectomy (OR 2.28, 95% CI 1.37, 3.79), previous oral contraceptive use (OR 1.76, 95% CI 1. 03, 3.01), HRT prescription to prevent osteoporosis (OR 1.81, 95% CI 1.04, 3.13), opinion that HRT prevents health problems (OR 3.22, 95% CI 1.57, 6.63), opinion that HRT is associated with health risks (OR 0.23, 95% CI 0.08, 0.65), and opinion that HRT has cosmetic benefits (OR 2.52, 95% CI 1.45, 4.40) were statistically significantly associated with long-term HRT. Women surveyed most often reported side effects and weight gain (each about 30%) as reasons for discontinuation, followed by possible health risks and dislike of menstrual bleeding or hormones (each about 15%). CONCLUSION: Ovariectomy, hysterectomy, and opinions about benefits and disadvantages of HRT were the most important determinants of long-term use, whereas women themselves mentioned side effects and weight gain most frequently as reasons for discontinuing it.

Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone replacement therapy use.

This study addresses attitudes towards changes in menstrual bleeding patterns caused by oral contraceptives (OC) or hormone replacement therapy (HRT) and preferred changes in bleeding pattern with and without use of OC or HRT in relation to reproductive age group. Data were collected by means of telephone interviews with 325 women in each of four age groups (15-19, 25-34, 45-49, and 52-57 years). In total, 80.5% of currently menstruating women preferred one or more changes in bleeding pattern such as less painful, shorter, or less heavy periods, or amenorrhea. The majority of the menstruating women in all age groups preferred to have a bleeding frequency of less than once a month or never, whether the bleeding was spontaneous or induced by OC. In the case of HRT, amenorrhea was most preferred. These findings with respect to preferred bleeding frequency and OC may have important implications for health care providers and for future contraception development.

PIP: This study addresses attitudes toward changes in menstrual bleeding patterns caused by oral contraceptives (OCs) or hormone replacement therapy (HRT) and preferred changes in bleeding pattern with and without use of OCs or HRT in relation to reproductive age group. A survey on 325 Dutch women from each of four age categories (15-19, 25-34, 45-49, and 52-57 years) was conducted through telephone interviews. Results showed that OC users and menstruating women prefer one or more changes in bleeding characteristics such as less painful, shorter, or lighter periods. It was less significant in the non-OC users in all age groups (75.1% vs. 86.3%, p = 0.016, in women aged 15-19 years; 60.0% vs. 72.3%, p = 0.030, in women aged 25-34 years; 50.9% vs. 74.5%, p = 0.002, in women aged 45-49 years). Most women would prefer a bleeding frequency of less than once a month or never. The proportion of women who reported amenorrhea as a positive consequence of OC/HRT use increased with age. These findings provide significant implications for health care providers in future contraception development.

Psychosocial experiences in women facing fertility problems--a comparative survey.

In a survey involving 281 patients awaiting assisted reproduction treatment at five centres in three countries, and 289 population controls, we investigated whether the patients had experienced more negative emotional feelings and negative emotional impact during periods when they were attempting to conceive as compared with the controls, and whether there was any difference in their well-being at the time of consultation. The study was performed in the context of currently divergent views as to the burden of fertility problems. The survey was carried out using questionnaires of the self-administration type. Women with fertility problems did in fact consistently report a higher prevalence of negative emotions than the controls with reference to the periods during which they had been trying to conceive. Patients reported more changes in interpartner relationships (either negative or positive). Sexuality was negatively affected among the patients. At the time of consultation, the patients had less favourable scores than the controls on scales for depressed mood, memory/concentration, anxiety and fears, as well as for self-perceived attractiveness. One in four (24.9%) of the patients had scores indicating depressive disorders as compared with only 6.8% of the controls. Current well-being was even more markedly affected in patients with previous unsuccessful in-vitro fertilization (IVF) experience. The 'infertility' life event was perceived as severe by both patients and controls. Both prior to consultation and during diagnosis and treatment, women with fertility problems had a higher prevalence of reported negative psycho-emotional experiences than women without fertility problems.

Menstrual cycle length preceding menopause in relation to age at menopause.

OBJECTIVES: In one of the earlier hypotheses of the etiology of breast cancer (Korenman's 'oestrogen window' hypothesis (1981)), it was assumed that women with a later age at menopause have a longer period with irregular cycles preceding menopause than women with an early menopause. This assumption was tested in a prospective study. METHODS: Subjects were 628 women, born between 1932 and 1941, who had participated in a breast cancer screening project in Utrecht, The Netherlands (the DOM-project) in 1982-1985, and who were still menstruating at that time. The women had filled out a questionnaire and a menstrual calendar every 2 years to determine their age at menopause prospectively. The women had not used oral contraceptives or medicines for menopausal complaints and had reached natural menopause by 1992. The median of the mean menstrual cycle length per woman and the median of the standard deviation of the mean menstrual cycle length per woman were plotted against number of years prior to menopause in three categories of age at menopause (44-49; 50-54; 55-59). RESULTS: During the 9 years prior to menopause, women with a late age at menopause have a somewhat higher mean menstrual cycle length than women with a younger age at menopause (P = 0.0008). Cycle length variability in the 9 years prior to menopause is not statistically significantly different between the three categories of age at menopause (P = 0.16). CONCLUSIONS: The assumption that women with a late age at menopause have a longer period with irregular cycles than women with an earlier age at menopause was not corroborated by our results.

Breast-cancer incidence in relation to height, weight and body-fat distribution in the Dutch "DOM" cohort.

In a cohort of 11,663 participants in a breast-cancer screening program, height, weight, waist circumference and hip circumference were measured, and information about menstrual and reproductive history was obtained by questionnaire. After exclusion of 83 women with unclear menopausal status, the subjects were divided into 3 sub-cohorts: 5,891 women who were pre-menopausal at the time of data collection, 3,521 women who had entered the study after natural menopause, and 2068 women who had been hysterectomized and/or ovariectomized. After a median follow-up of 10.6 years, 147, 76 and 52 incident cases of breast cancer were detected in the 3 respective sub-cohorts. No statistically significant association was found in any of the sub-cohorts between breast-cancer risk and height, weight, body-mass index (BMI) or hip circumference. In the sub-cohort of women with natural menopause, however, risk of breast cancer was positively and significantly associated with the ratio of waist-to-hip circumferences (WHR) (RR = 2.63 for upper vs. lower quartile), and this association did not change after adjustment for variations in disease risk related to body height and weight. Although similar to observations in other cohort studies showing positive associations between obesity and breast-cancer risk in post-menopausal women, our results are different, in that WHR and not BMI appears to be the more specific indicator of breast-cancer risk.

Validity and reproducibility of self-reported age at menopause in women participating in the DOM-project.

OBJECTIVES: To study validity and reproducibility of self reported age at menopause. METHODS: Subjects were 1003 and 4892 Dutch women respectively aged 58-73, who participated in a population-based breast cancer screening project. The median time since menopause was 7 years for the validity study. The time span between the two questionnaires in the reproducibility study was 7-9 years. RESULTS: Of the women with a natural menopause, 70% recalled their age at menopause correctly to within one year. For women with a surgical menopause this percentage was 80%. The validity decreased with increasing number of years since menopause. Reproducibility to within one year was 71% for women with a natural menopause and 79% for women with a surgical menopause; 95% of the women were consistent in reporting whether they had had a natural or a surgical menopause. CONCLUSIONS: As a consequence of this misclassification, the effect of age at menopause may be underestimated in studies relating self reported age at menopause to disease occurrence or mortality.

Obesity and fat distribution in relation to hot flashes in Dutch women from the DOM-project.

The authors studied obesity and fat distribution in relation to the occurrence of hot flashes in a population-based study comprising 2904 women aged 40-44 and 569 women aged 54-69 presenting for mammographic screening (the DOM-project). Women aged 40-44 in the upper tertiles of Quetelet's index and waist/hip ratio reported hot flashes significantly more often than women in the respective lower tertiles. These associations were independent of each other and independent of age. After adjustment for age, waist/hip ratio and menopausal status, the odds ratio comparing the upper tertile of Quetelet's index to the lower tertile was 1.70 (95% confidence interval, 1.30-2.21). After adjustment for age, Quetelet's index and menopausal status, the odds ratio comparing the upper tertile of waist/hip ratio to the lower tertile was 1.37 (95% CI, 1.05-1.78). In women aged 54-69 no significant associations between Quetelet's index and complaints of hot flashes were observed. Women in the upper tertile of waist/hip ratio reported hot flashes more often than women in the lower tertile, but this result was not significant (OR 1.38; 95% CI, 0.87-2.22).

Regularity and length of menstrual cycles in women aged 41-46 in relation to breast cancer risk: results from the DOM-project.

The effect of regularity and length of the menstrual cycle on breast cancer risk was studied prospectively in 78 cases and 383 age-matched controls who participated in a breast cancer screening programme, the DOM-project, in Utrecht, the Netherlands. Before entering the screening programme when they were aged 41-46, the women kept a menstrual calendar during at least three consecutive cycles. Cycles were considered to be irregular if any of three cycles was shorter than 21 days or longer than 35 days and/or if variation between cycle lengths was more than five days. Women with irregular cycles had a significantly reduced risk of breast cancer (odds ratio = 0.44; 95% confidence interval 0.22-0.86) after adjustment for age at menarche, age at first birth, parity, Quetelet's index and family history of breast cancer. Among regularly menstruating women, long cycles (28 days or more) were not significantly associated with increased risk of breast cancer (odds ratio 1.17; 95% confidence interval 0.66-2.09). To the extent that irregular menstrual cycles reflect anovulatory cycles, our findings support the hypothesis that the cumulative number of regular ovulatory cycles increases breast cancer risk.

Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project.

The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness. No significant differences in survival time between more obese (Quetelet's index > or = 26 kg/m2) and leaner (Quetelet's index < 26 kg/m2) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors. The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.

Body fat distribution in relation to breast cancer in women participating in the DOM-project.

The association between body fat distribution and breast cancer risk was studied in 5923 pre- and 3568 post-menopausal women, participating in a breast cancer screening project (the DOM-project in Utrecht, the Netherlands). Cases were fifty six premenopausal women and thirty eight postmenopausal women with breast cancer detected at screening or afterwards. Controls were women participating in the breast cancer screening project without breast cancer. Waist- and hip circumferences, height and weight were measured at screening, before diagnosis of breast cancer. In postmenopausal women the estimated relative risk of women in the upper tertile of waist/hip ratio compared with women in the lower tertile was 1.89 (95% CI 0.80-4.48), (test for trend p = 0.11). The estimated relative risk of women in the upper tertile of waist circumference compared with women in the lower tertile was 2.86 (95% CI 1.12-7.32), (test for trend p = 0.08). The association between waist circumference and breast cancer was stronger than the association between any of the other anthropometric variables and breast cancer. In premenopausal women the association between fat distribution and breast cancer was equivocal.

A prospective study on obesity and subcutaneous fat patterning in relation to breast cancer in post-menopausal women participating in the DOM project.

The associations of body fat and body fat distribution with breast cancer risk were examined in a prospective study in 9,746 post-menopausal women with a natural menopause, aged 49-66 at intake, participating in a breast cancer screening project (the DOM project in Utrecht). During a follow-up period of 15 years (mean follow-up time 12.5 years) 260 women developed breast cancer. Fat distribution, assessed by contrasting groups of subcapsular and triceps skinfold thickness, was found to be unrelated to breast cancer incidence. No significant relationship between body fat, measured either by weight, Quetelet's index, triceps skinfold or subscapular skinfold, and breast cancer risk was found when analysed in quartiles. However, women in the upper decile compared with the lower decile of the distribution of Quetelet's index were found to have a 1.9 times (95% CI 1.1-3.3) higher risk for breast cancer. These results seemed to be in contrast with the significant positive association between fatness, analysed in quartiles, and breast cancer observed in a cross-sectional study, based on mammographic screening, carried out previously in the same population. Although the differences between the present, prospective, study and our cross-sectional study may be due to chance it may be that there are differences between characteristics of breast cancer detected at screening and subsequently, which influence the associations between measures of fatness and risk of breast cancer.

D.B. Kagenaar and the ophthalmometer by Javal-Schiøtz.

In the years 1881-1890 the Utrecht instrumentmaker D.B. Kagenaar, laboratory attendant of Donders and Snellen, played an important role in the introduction on the German market of the ophthalmometer developed by Javal and Schiøtz.