C.W.N. Looman

Delaying childbearing: effect of age on fecundity and outcome of pregnancy.

OBJECTIVES--To study the age of the start of the fall (critical age) in fecundity; the probability of a pregnancy leading to a healthy baby taking into account the age of the woman; and, combining these results, to determine the age dependent probability of getting a healthy baby. DESIGN--Cohort study of all women who had entered a donor insemination programme. SETTING--Two fertility clinics serving a large part of The Netherlands. SUBJECTS--Of 1637 women attending for artificial insemination 751 fulfilled the selection criteria, being married to an azoospermic husband and nulliparous and never having received donor insemination before. MAIN OUTCOME MEASURES--The number of cycles before pregnancy (a positive pregnancy test result) or stopping treatment; and result of the pregnancy (successful outcome). RESULTS--Of the 751 women, 555 became pregnant and 461 had healthy babies. The fall in fecundity was estimated to start at around 31 years (critical age); after 12 cycles the probability of pregnancy in a woman aged greater than 31 was 0.54 compared with 0.74 in a woman aged 20.31. After 24 cycles this difference had decreased (probability of conception 0.75 in women greater than 31 and 0.85 in women 20.31). The probability of having a healthy baby also decreased--by 3.5% a year after the age of 30. Combining both these age effects, the chance of a woman aged 35 having a healthy baby was about half that of a woman aged 25. CONCLUSION--After the age of 31 the probability of conception falls rapidly, but this can be partly compensated for by continuing insemination for more cycles. In addition, the probability of an adverse pregnancy outcome starts to increase at about the same age.

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.

Basal follicle-stimulating hormone levels are of limited value in predicting ongoing pregnancy rates after in vitro fertilization.

OBJECTIVEnTo evaluate whether basal FSH (bFSH; measured on menstrual day 1-4) adds relevant clinical information to the prediction of ongoing pregnancy rates (OPRs) after IVF, once age and diagnostic characteristics have been taken into account.nnnDESIGNnRetrospective.nnnSETTINGnAcademic fertility center.nnnPATIENT(S)n435 women undergoing their first IVF cycle.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nOngoing pregnancy rate.nnnRESULT(S)nThe likelihood ratio of bFSH as a single prognosticator for treatment failure at a cutoff level of 15 IU/L was 3.87. The proportion of patients with such a bFSH level was 5%. Multivariate logistic regression analysis selected age, bFSH level, and infertility diagnosis as relevant predictors of ongoing pregnancy. When compared to a predictive model for OPRs based on age and infertility diagnosis, the inclusion of bFSH into this model helped to identify more patients (22 vs. 1) whose predicted OPR decreased from a low level (5%-12%) towards an extremely low level (<5%).nnnCONCLUSION(S)nAn acceptable performance of bFSH as a single test to predict treatment failure is only obtained above a high cutoff level. Thus, the number of patients for whom bFSH provides relevant information is small. The predictive model including bFSH identified significantly more patients with an extremely poor prognosis than did the predictive model without bFSH. However, predictions based solely on age and infertility diagnosis usually were already poor in these patients. Measurement of bFSH adds little in only a few patients and is, therefore, debatable.

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.