I. den Tonkelaar

Anti-Müllerian hormone is a promising predictor for the occurrence of the menopausal transition.

Objective: Age at menopause and age at the start of the preceding period of cycle irregularity (menopausal transition) show considerable individual variation. In this study we explored several markers for their ability to predict the occurrence of the transition to menopause. Design: A group of 81 normal women between 25 and 46 years of age visited the clinic two times (at T1 and T2) with an average interval of 4 years. All had a regular menstrual cycle pattern at T1. At T1, anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B and estradiol (E2) were measured, and an antral follicle count (AFC) was made during the early follicular phase. At T2, information regarding cycle length and variability was obtained. Menopause transition was defined as a mean cycle length of less than 21 days or more than 35 days or as a mean cycle length of 21 to 35 days, but with the next cycle not predictable within 7 days during the last half year. A logistic regression analysis was performed, with the outcome measure as menopause transition. The area under the receiver operating curve (ROCAUC) was calculated as a measure of predictive accuracy. Results: In 14 volunteers, the cycle had become irregular at T2. Compared with women with a regular cycle at T2, these women were significantly older (median 44.7 vs 39.8 y, P < 0.001) and differed significantly in AFC, AMH, FSH, and inhibin B levels assessed at T1. All parameters with the exception of E2 were significantly associated with the occurrence of cycle irregularity; AMH, AFC, and age had the highest predictive accuracy (ROCAUC 0.87, 0.80, and 0.82, respectively). After adjusting for age, only AMH and inhibin B were significantly associated with cycle irregularity. Inclusion of inhibin B and age to AMH in a multivariable model improved the predictive accuracy (ROCAUC 0.92). Conclusions: The novel marker AMH is a promising predictor for the occurrence of menopausal transition within 4 years. Adding inhibin B improved the prediction. Therefore, AMH alone or in combination with inhibin B may well prove a useful indicator for the reproductive status of an individual woman.

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

Abstract 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 Quetelets 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 Quetelets index to the lower tertile was 1.70 (95% confidence interval, 1.30-2.21). After adjustment for age, Quetelets 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 Quetelets 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).

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

SummaryThe 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 (Quetelets index ≥ 26 kg/m2) and leaner (Quetelets 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

SummaryThe association between body fat distribution and breast cancer risk was studied in 5923 pre- and 3568 postmenopausal 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 I 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, Quetelets 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 Quetelets 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.

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

SummaryThe 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, Quetelets 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 breast cancer in postmenopausal women participating in the Diagnostic Investigation of Mammary Cancer Project.

Associations of body fat and body fat distribution with breast cancer were studied in 16,355 postmenopausal women with a natural menopause, aged 49 to 68 years, participating in a breast cancer screening project (the Diagnostic Investigation of Mammary Cancer [DOM] project in Utrecht, The Netherlands). One hundred nineteen women had breast cancer detected at first screening. Fat distribution was assessed by contrasting groups of sub‐scapular and triceps skinfold thickness. No relationship between fat distribution and breast cancer was found. After adjustment for age, women in the highest quartile of Quetelets index (QI) (weight/height2) had an odds ratio of 1.65 (95% confidence interval [CI], 0.97 to 2.81) compared with women in the the lowest quartile (test for trend, P < 0.05). For subscapular skinfold and triceps skinfold, the odds ratios were 2.23 (95% CI, 1.28 to 3.91) and 2.01 (95% CI, 1.21 to 3.32), respectively, comparing the highest with the lowest quartile. The authors conclude that in postmenopausal women, overall obesity is associated with increased risk of breast cancer, whereas fat distribution, as measured by contrasting groups of subscapular and triceps skinfold thicknesses, is not related to breast cancer. Cancer 1992; 69:2663‐2667.

A prospective study on corpus luteum function and breast cancer risk

A case-control study incorporated within a cohort study was undertaken to test the hypothesis that anovulation or decreased luteal function is associated with increased risk of breast cancer. A large population (n = 12,000) of apparently healthy women aged 40-49 collected a specimen of urine on day 22 of 3 consecutive menstrual cycles, or, in cases of amenorrhea, on 3 arbitrarily chosen days. These samples were stored at -20 degrees C. Subsequent screening of the women by mammography revealed 34 cases of breast cancer, and over the next 4 years a further 34 cases were reported to the cancer registry. Urine samples from 53 of these cases were assayed for pregnanediol and creatinine, and the results were compared with those for an equal number of matched controls. No differences between these groups were found in the pregnanediol/creatinine ratio. We conclude that our results do not support the hypothesis that women with luteal insufficiency are at increased risk for breast cancer. However, since breast cancer patients tend to have a later menopause than controls, the possibility cannot be excluded that breast cancer patients continue to have ovulatory cycles for a longer period during reproductive life. Such a finding--opposite to the working hypothesis--would complicate the interpretation of the results.

Association between ovulation induction and early menopause--a cohort effect?

Dear Sir, We read the article by Pines et al., in which the interesting issue was addressed whether hormonal therapy for infertility influences age at menopause [1]. In this article it was suggested that women undergoing induction of ovulation might suffer an early menopause. However, I have serious concerns about the validity of this study. Participants in this study were postmenopausal women visiting a menopause clinic. Women with a history of ovulation induction (n /31) were compared with women who never experienced infertility treatment (control group) (n /200). The mean age at menopause was 46.4 years in the ovulation induction group and 50.0 years in the control group. However, such a comparison is only valid if women in both groups have had equal opportunity to reach menopause. To illustrate this point let us compare the mean age at menopause of women in the birth cohort 1948 /1953 with women in the birth cohort 1942 /1947. If we use questionnaire data from 1999, the (spurious) result will be that women in the younger birth cohort have a lower mean age at menopause than women in the older birth cohort. This artifact arises from the fact that women in the younger birth cohort are 46 /51 years of age in 1999 and only those who have reached menopause before 51 years will be able to report age at menopause. Women with a later age at menopause did not yet have the opportunity to reach (and report) menopause. The older birth cohort consists of women who are 52 /57 years of age in 1999 and includes also women who have (and are able to report) a later age at menopause. It may well be that women with a history of ovulation induction belong to a younger birth cohort than women who never experienced fertility treatment. The finding of a lower mean age at menopause in this group would then be an artifact. Therefore, I would like to know the distributions of the year of birth of the two groups and I am very interested to see the results after adjustment for year of birth.