E.R. te Velde

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.

Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women

CONTEXT It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma. OBJECTIVE The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause. DESIGN AND SETTING We conducted a long-term follow-up study at an academic hospital. PARTICIPANTS A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria. INTERVENTIONS Anti-Müllerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried. MAIN OUTCOME MEASURES Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause. RESULTS A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level. CONCLUSIONS AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.

Age-Related Changes in the Ultrastructure of the Resting Follicle Pool in Human Ovaries

Abstract Age-related decline of fertility in women is the result of the decline in both quantity and quality of the resting ovarian follicle pool. The aim of the present study was to determine whether the decline of follicle quality with age is reflected by ultrastructural changes in the resting follicle pool. Ovarian biopsy specimens were obtained by laparoscopy from seven healthy women aged 25–32 yr (young group) and from 11 healthy women aged 38–45 yr (advanced-age group). A total of 182 resting follicles from the young group were compared with 81 resting follicles from the advanced-age group for signs of age-related changes by transmission-electron microscopy. The ooplasmic fraction of vacuoles was increased (P = 0.02), and the fraction of mitochondria decreased (P = 0.005), in the advanced-age group. Also, the density of the mitochondrial matrix (P < 0.001) and the frequency of dilated smooth endoplasmic reticulum (SER; P = 0.001) and Golgi complex (P = 0.02) were increased with age. The frequencies of ruptured mitochondrial membranes (P = 0.001) and dilated SER (P = 0.003) were increased with age in the granulosa cells. Overall follicle-quality scores, which should reflect atretic changes, were not different for the young and advanced-age groups. In conclusion, in resting follicles, the morphological changes with age are different from the changes seen in quality decline by atresia. The morphological changes with age specifically involved the mitochondria, the SER, and the Golgi complex, and they may be the cause of atresia on initiation of follicular growth because of the substantial increase in metabolic requirements.

Age at menopause as a marker of reproductive ageing

Ages of menopause and of the preceding reproductive events such as the beginning of subfertility and infertility, are likely to be dictated by the process of follicle depletion leading to loss of oocyte quantity and quality. To some extent this process is influenced by lifestyle factors like smoking, and possibly also by the use of oral contraceptives. Genetic factors and possibly also events during intrauterine life, probably play a more important role in the age-dependent decrease of female fertility.

Pesticide exposure and decreased fertilisation rates in vitro

The effect of paternal occupational exposures on fertilising ability was investigated in 836 couples who sought in-vitro fertilisation treatment. Fertilisation rates were significantly decreased for couples with paternal pesticide exposure.

Ultrastructure of the Resting Ovarian Follicle Pool in Healthy Young Women

Abstract In humans, follicle quantity and quality decline with age by atresia. In the present study we aimed to describe the quality of the follicle pool through an ultrastructural investigation of resting follicles in young healthy women. From ovarian biopsies of 7 women aged 25–32 yr, 182 small follicles were morphometrically assessed for various signs of atresia. Morphometric variables were analyzed by principal components analysis (PCA) to demonstrate correlations between variables and to construct an objective follicle score. One third of small follicles consisted of primordial follicles. Nucleus:cell ratios remained constant for oocytes and granulosa cells from primordial to primary follicles, suggesting that follicles up to primary stages belong to the resting pool. The distribution of follicle quality scores as derived from PCA showed that most follicles were of good quality and with little signs of atresia. Atresia in resting follicles appears to be a necrotic process, starting in the ooplasma. Early atresia was characterized by increasing numbers of multivesicular bodies and lipid droplets, dilation of smooth endoplasmic reticulum and Golgi, and irregular mitochondria with changed matrix density. In progressive atresia mitochondrial membranes ruptured, oocyte nuclear membranes were indented or ruptured, and the ooplasma showed extensive vacuolarization. The early involvement of mitochondria in this process suggests that damage is induced by oxygen radicals. PCA follicle quality scores can be reliably approximated using a reduced number of seven morphometric variables, which were selected by stepwise forward analysis. The algorithm to calculate these follicle scores is presented.

Europe the continent with the lowest fertility

INTRODUCTION Although fertility rates are falling in many countries, Europe is the continent with the lowest total fertility rate (TFR). This review assesses trends in fertility rates, explores possible health and social factors and reviews the impact of health and social interventions designed to increase fertility rates. METHODS Searches were done in medical and social science databases for the most recent evidence on relevant subject headings such as TFR, contraception, migration, employment policy and family benefits. Priorities, omissions and disagreements were resolved by discussion. RESULTS The average TFR in Europe is down to 1.5 children per woman and the perceived ideal family size is also declining. This low fertility rate does not seem directly caused by contraception since in Northern and Western Europe the fertility decline started in the second half of the 1960s. Factors impacting on lower fertility include the instability of modern partnerships and value changes. Government support of assisted human reproduction is beneficial for families, but the effect on TFR is extremely small. Government policies that transfer cash to families for pregnancy and child support also have small effects on the TFR. CONCLUSIONS Societal support for families and for couples trying to conceive improves the lives of families but makes no substantial contribution to increased fertility rates.

Current Smoking at Menopause Rather Than Duration Determines the Onset of Natural Menopause

Background: Smoking has frequently been associated with early menopause. However, studies of this association have been inconclusive with regard to duration and intensity of smoking. A major problem in analyzing the effect of smoking duration on menopausal age is that both exposure and outcome are age-dependent. Methods: We calculated age-specific rates for categories of smoking duration and subsequently computed the rate ratios for occurrence of menopause. We were thus able to model the effect of smoking duration on 2 time scales without assumptions of linearity. We used data from a Dutch population-based cohort comprising 5544 women age 49–70 years who had experienced natural menopause. Results: The rate ratio (RR) for occurrence of menopause was increased in women who smoked in the year of menopause (RR = 1.41; 95% confidence interval = 1.32–1.50). The rate ratio of former smokers was similar to women who never smoked (0.95; 0.89–1.02). Prolonged exposure of smoking did not materially affect the risk of menopause, although the daily number of cigarettes currently smoked could increase the risk. Conclusion: Perimenopausal smoking is apparently more important than smoking history in explaining an earlier age of onset of menopause among women who smoke.

Ovarian reserve tests in infertility practice and normal fertile women

The decline in fecundity with the age of the woman is mainly attributed to the loss of follicles from the ovary and a decrease in oocyte quality. Evaluation of the aging status of the ovary in an individual woman has been hampered by a lack of knowledge with regard to the relative contribution of these two factors. Most if not all so called ovarian reserve tests (ORT) reflect indirectly the remaining follicle pool in the ovary. Direct a priori assessment of oocyte quality is not possible to date. In this section the predictive value of several ovarian reserve tests for the outcome of fertility treatment is listed and commented. In addition, the study of several of the ORTs in normal, fertile women is described. From the data presented dynamic testing of the ovarian function by the clomiphene citrate and GnRH agonist stimulation test, as well as static testing by the use of ultrasound based antral follicle counts seem to offer the highest clinical value. Studies performing direct comparison of these tests are needed, as well as analysis of the way these tests should direct decision making in infertility diagnosis and treatment.

General ageing and ovarian ageing

The age related decrease in female fertility is associated with a decrease in follicle numbers and oocyte quality. Meiotic division errors, mitochondrial DNA mutations and ageing itself have been suggested to play a part in the age associated reduction in oocyte quality. During the past decades several hypothesis have been proposed, trying to explain the underlying mechanisms. However, none of them is yet conclusive. This review will consider the main hypotheses regarding the age related reduction in oocyte quality. This will be reviewed together with recent results of studies analysing a possible relationship between ageing and ovarian ageing. On the basis of our own results and those presented in the literature, it is concluded that ovarian ageing may only be related to specific aspects of general ageing.