Natural conception: repeated predictions over time.

STUDY QUESTION: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility? SUMMARY ANSWER: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic. WHAT IS KNOWN ALREADY: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management. STUDY DESIGN, SIZE, DURATION: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup. LIMITATIONS, REASONS FOR CAUTION: The dynamic prediction model needs to be validated in an external population. WIDER IMPLICATIONS OF THE FINDINGS: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup. STUDY FUNDING/COMPETING INTERESTS: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.

Clinical prediction models to inform individualized decision-making in subfertile couples: a stratified medicine approach.

Infertility is defined as failure to conceive after 1 year of unprotected intercourse. This dichotomization into fertile versus infertile, based on lack of conception over 12-month period, is fundamentally flawed. Time to conception is strongly influenced by factors such as female age and whilst a minority of couples have absolute infertility (sterility), many are able to conceive without intervention but may take longer to do so, reflecting the degree of subfertility. This natural variability in time to conception means that subfertility reflects a prognosis rather than a diagnosis. Current clinical prediction models in fertility only provide individualized estimates of the probability of either treatment-independent pregnancy or treatment-dependent pregnancy, but do not take account of both. Together, prognostic factors which are able to predict natural pregnancy and predictive factors of response to treatment would be required to estimate the absolute increase in pregnancy chances with treatment. This stratified medicine approach would be appropriate for facilitating personalized decision-making concerning whether or not to treat subfertile patients. Published models are thus far of little value for decisions regarding when to initiate treatment in patients who undergo a period of, ultimately unsuccessful, expectant management. We submit that a dynamic prediction approach, which estimates the change in subfertility prognosis over the course of follow-up, would be ideally suited to inform when the commencement of treatment would be most beneficial in those undergoing expectant management. Further research needs to be undertaken to identify treatment predictive factors and to identify or create databases to allow these approaches to be explored. In the interim, the most feasible approach is to use a combination of previously published clinical prediction models.

Comparison of two models predicting IVF success; the effect of time trends on model performance.

STUDY QUESTION: How well does the recently developed UK model predicting the success rate of IVF treatment (the 2011 Nelson model) perform in comparison with a UK model developed in the early 1990s (the Templeton model)? SUMMARY ANSWER: Both models showed similar performance, after correction for the increasing success rate over time of IVF. WHAT IS KNOWN ALREADY: For counselling couples undergoing IVF treatment it is of paramount importance to be able to predict success. Several prediction models for the chance of success after IVF treatment have been developed. So far, the Templeton model has been recommended as the best approach after having been validated in several independent patient data sets. The Nelson model, developed in 2011 and characterized by the largest development sample containing the most recently treated couples, may well perform better. STUDY DESIGN, SIZE, DURATION: We tested both models in couples that were included in a national cohort study carried out in the Netherlands between the beginning of January 2002 and the end of December 2004. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed the IVF cycles of Dutch couples with primary infertility (n = 5176). The chance of success was calculated using the two UK models that had been developed using the information collected in the Human Fertilisation and Embryology Authority database. Women were treated in 1991-1994 (Templeton) or 2003-2007 (Nelson). The outcome of success for both UK models is the occurrence of a live birth after IVF but the outcome in the Dutch data is an ongoing pregnancy. In order to make the outcomes compatible, we used a factor to convert the chance of live birth to ongoing pregnancy and use the overall terms 'success or no success after IVF'. The discriminative ability and the calibration of both models were assessed, the latter before and after adjustment for time trends in IVF success rates. MAIN RESULTS AND THE ROLE OF CHANCE: The two models showed a similarly limited degree of discriminative ability on the tested data (area under the receiver operating characteristic curve 0.597 for the Templeton model and 0.590 for the Nelson model). The Templeton model underestimated the success rate (observed 21% versus predicted 14%); the Nelson model overestimated the success rate (observed 21% versus predicted 29%). When the models were adjusted for the changing success rates over time, the calibration of both models considerably improved (Templeton observed 21% versus predicted 20%; Nelson observed 21% versus predicted 24%). LIMITATIONS, REASONS FOR CAUTION: We could only test the models in couples with primary infertility because detailed information on secondary infertile couples was lacking in the Dutch data. This shortcoming may have negatively influenced the performance of the Nelson model. WIDER IMPLICATIONS OF THE FINDINGS: The changes in success rates over time should be taken into account when assessing prediction models for estimating the success rate of IVF treatment. In patients with primary infertility, the choice to use the Templeton or Nelson model is arbitrary.

Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study.

STUDY QUESTION: Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? SUMMARY ANSWER: No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. WHAT IS KNOWN ALREADY: Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. STUDY DESIGN, SIZE, DURATION: This cohort study included men and women born around the time of the Dutch famine of 1944-1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. MAIN RESULTS AND THE ROLE OF CHANCE: Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the NHLBI/NIH (R01 HL-067914). TRIAL REGISTRATION NUMBER: Not applicable.

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.

[Sensible family planning: pitfalls and dilemmas]. / Verstandige gezinsplanning: valkuilen en dilemma's.

In a recent article in this journal it was stated that Dutch women were sensible in having their first child between the ages of 25 and 35 years. One of the conclusions was that associated health risks increase after the age of 35 but are still acceptable even at the age of 40. We demonstrate that these conclusions were based on flawed assumptions. Postponing pregnancy until after the age of 30 increases the risks of infertility and breast cancer. Motherhood at a later age is associated with an increase in obstetrical complications, miscarriage and other adverse effects on the child. Therefore, for couples planning a family with 2 children or more, it would be sensible to have the first pregnancy not long after the mother reaches the age of 30 years, or even earlier. Couples should be informed on the risks of late parenthood in order to be able to take the right decisions concerning family planning.

[Reduction of patient discomfort, risks and costs, but not pregnancies, by a mild strategy for in-vitro fertilisation]. / Minder risico's, patiëntenongemak en kosten, maar niet minder zwangerschappen in de milde behandelstrategie voor ivf.

OBJECTIVE: To compare a so-called mild in-vitro fertilisation (IVF) treatment strategy with the standard IVF treatment on the following aspects: the chance of a pregnancy resulting in full-term live birth within 1 year, patient discomfort, multiple pregnancies, and costs. DESIGN: Randomised, open-label, prospective trial (www.controlledtrials.com, number ISRCTN35766970). METHOD: 404 patients were assigned to undergo either a mild treatment, consisting of ovarian stimulation with a gonadotrophin releasing hormone (GnRH) antagonist combined with single embryo transfer, or the standard treatment consisting of prolonged stimulation with a GnRH agonist combined with the transfer of two embryos. The primary outcome measures were: (1) the percentage of cumulative pregnancies within one year after randomisation leading to full-term live birth; (2) total costs per couple and child up to 6 weeks after expected delivery; and (3) overall patient discomfort. Analysis was done according to the intention-to-treat principle and was intended to show that the mild treatment was not inferior to the standard treatment; the non-inferiority threshold was -12.5%. RESULTS: The proportion of cumulative pregnancies resulting in full-term live birth after 1 year was 43.4% in the mild and 44.7% in the standard treatment group. The lower limit of the one-sided 95% confidence interval was equal to -9.8%. The respective proportion of couples with multiple pregnancies was 0.5% versus 13.1% (p < 0.0001), and the average total costs were Euro 8,333.- versus Euro 10,745.- (difference: Euro 2,412.-, 95% CI: 703-4,131). There were no statistically significant differences between the groups with regard to anxiety, depression, physical discomfort, and sleep quality. CONCLUSION: After 1 year of treatment, the cumulative percentage of pregnancies leading to full-term live birth and the total patient discomfort were the same for the mild treatment (average 2.3 IVF-cycles) and the standard treatment (average 1.7 IVF-cycles). The mild treatment significantly reduced the number of multiple pregnancies and the overall costs.

[The consequences of postponing pregnancy]. / Gevolgen van uitstel van zwangerschap.

The postponement of childbearing is determined by societal factors and is related to the fact that it is often difficult for women to combine an education, a job or a career with having children and taking care of a family. Especially gynaecologists are increasingly confronted with women who undergo the medical consequences of such postponement. Postponing the first pregnancy is accompanied by an increased risk of unwanted infertility. If women do succeed in becoming pregnant later in life, there is an increased risk of complications during pregnancy and delivery. The child runs a greater risk of chromosomal aberrations and of mental and physical handicaps related to increased numbers of premature births and fertility treatments. All these problems begin to increase after age 30, but especially after age 35. Finally, the risk of breast cancer is also increased if a woman delays the birth of her first child or remains childless.

Cumulative live birth rates following IVF in 41- to 43-year-old women presenting with favourable ovarian reserve characteristics.

For women aged 41-43 years old, success rates in IVF are generally poor. This study aimed to assess cumulative live birth rate related to treatment costs over a maximum of three IVF cycles in selected women who were considered to still have adequate ovarian reserve. Fifty-five patients (38% of the total cohort, n = 144) were excluded from IVF treatment based on low antral follicle count (<5 follicles) and/or elevated basal FSH (>15 IU/l). Of those admitted, 66 (74%) actually started and completed a total of 125 IVF/intracytoplasmic sperm injection cycles. Treatment resulted in 10 live births (8% per cycle). Kaplan-Meier survival analysis revealed a realistic cumulative live birth rate after three cycles of 17%. The direct medical costs per live birth were calculated to be approximately 44,000 euro. These results show that selection towards favourable ovarian reserve status in the female age group 41-43 years yielded disappointing results in terms of cumulative live birth rates after IVF. In view of the costs raised per live birth, improvement of selection parameters for treatment in this age group is warranted.

Prevention of multiple pregnancies after IVF in women 38 and older: a randomized study.

The objective of this study was to answer the question of whether a double instead of triple embryo transfer strategy in patients over 38 years would substantially reduce the number of multiple pregnancies while maintaining the chance of a term live birth at an acceptable level. A randomized controlled two-centre trial was performed. Forty-five patients, 38 years or older, were randomized. Double embryo transfer over a maximum of four cycles (DET group) or triple embryo transfer over a maximum of three cycles (TET group) was performed. The cumulative term live birth rate was 47.3% after four cycles in the DET group and 40.5% after three cycles in the TET group. The difference between the DET and the TET group was 6.8% in favour of the DET group (95% CI -25 to 38). The multiple pregnancy rates in the DET and TET group were 0% (95% CI 0 to 24) and 30% (95% CI 7 to 65) respectively (P = 0.05). In the DET patients, the mean number of treatment cycles was 2.9 compared with 2.1 in the TET group (P = 0.01). In women of 38 years and older, double embryo transfer after IVF may result in similar cumulative term live birth rates compared with triple embryo transfer, provided that a higher number of treatment cycles is accepted.

Anti-Müllerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation.

CONTEXT: Anti-Müllerian hormone (AMH), a quantitative marker for ovarian reserve, has been suggested to be independent of the classical endocrine fluctuations of the menstrual cycle. OBJECTIVE: The objective of the study was to determine whether AMH levels are constant throughout the menstrual cycle, compared with those of FSH, LH, and estradiol. DESIGN/PATIENTS: Frequent blood sampling was performed in 44 fertile, regularly cycling, female volunteers during one full menstrual cycle. SETTING: The study was conducted at a university hospital. MAIN OUTCOME MEASURES: AMH, FSH, LH, and estradiol measurements were allocated to one of seven cycle phases, and a multilevel analysis was performed. Consistent fluctuation patterns were tested by fitting sine patterns to the data. Finally, the frequency in which randomly selected individual samples would remain in one of five preset level categories (quintiles) for each of the variables was studied. RESULTS: A sine pattern fitted to the AMH data was not statistically significant (P = 0.40). In contrast, sine patterns for FSH, LH, and estradiol were highly significant. Comparing the seven cycle phases, no significant differences could be observed between phase-specific AMH levels (P = 0.06). Repeated selection of AMH samples for each individual showed that in 71.5% of selections, AMH values remained in the same quintile, whereas in 27.9% values fell in an adjacent quintile. CONCLUSIONS: AMH levels measured through a full menstrual cycle did not show consistent fluctuation patterns in contrast to levels of FSH, LH, and estradiol. Furthermore, random fluctuations were small, indicating that AMH can be relied on as a cycle-independent marker for ovarian reserve.

[The influence of sexual function on the chance of pregnancy]. / De invloed van seksueel functioneren op de kans om zwanger te worden.

There is a complex association between sexual behaviour and (in)fertility. Sexual dysfunction can cause a delay in conception, but can also be the result of not conceiving. If conception is not achieved, sexual function may become disturbed and can deteriorate further as the result of the hospital fertility protocol and medical intervention. In terms of fertility, optimal sexual function is important because it increases the chance of conception. The greatest chance of conception is achieved through sexual intercourse on multiple occasions during the fertile period, particularly on days with good quality cervical mucus, with the right interval between ejaculations (not too long and not too short), adequate arousal of both partners and without the use of artificial lubricants. Time and attentiveness are particularly important in the patient-physician contact to be able to properly advise couples on these matters.

Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF.

PURPOSE: To study the value of a single or repeated GnRH agonist stimulation test (GAST) in predicting outcome in IVF compared to basal ovarian reserve tests. METHODS: A total of 57 women was included. In a cycle prior to the IVF treatment, on day 3, an antral follicle count (AFC) was performed and blood taken for basal FSH, inhibin B and E2 measurements, followed by a subcutaneous injection of 100 microg triptorelin for the purpose of the GAST. Twenty-four hours later blood sampling was repeated. All the tests were repeated in a subsequent cycle. From the GAST E2 and inhibin B response were used as test parameters. The outcome measures were poor ovarian response and ongoing pregnancy. Group comparisons were done using the Mann-Whitney or chi-square test. Univariate and multivariate logistic regression was applied to assess which test revealed the highest predictive accuracy as expressed in the area under receiver-operating characteristic curve (ROC(AUC)). Clinical value was compared by calculating classical test characteristics for the best logistic models. RESULTS: All the basal and GAST variables were significantly different in the poor responders (n = 19) compared to normal responders (n = 38). In the univariate analysis on cycle 1 tests the AFC was the best predictor for poor ovarian response, while in cycle 2 the E2 response in the GAST performed best (ROC(AUC) of 0.91 for both). Multivariate analysis of the basal variables led to the selection of AFC and inhibin B in cycle 1, yielding a ROC(AUC) of 0.96. Mean E2 response was selected in a multivariate analysis of the repeated GAST variables (ROC(AUC) 0.91). At a specificity level of -0.90, several logistic models including GAST variables appeared to have a sensitivity (-0.80), positive predictive value (-0.82) and false positive rate (-0.18), comparable to a logistic model containing AFC and inhibin B. None of the test variables showed a significant relation with ongoing pregnancy. CONCLUSIONS: The GAST has a rather good ability to predict poor response in IVF. However, comparing the predictive accuracy and clinical value of the GAST with a day 3 AFC and inhibin B, it appeared that neither a single nor a repeated GAST performed better. In addition, the predictive ability towards ongoing pregnancy is poor. Therefore, the use of the GAST as a predictor of outcome in IVF should not be advocated.

Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial.

BACKGROUND: The aim of this study was to evaluate the effect of doubling the starting dose of gonadotrophins on the ovarian response in IVF patients with a low antral follicle count (AFC). METHODS: Fifty-two patients with an AFC of <5 follicles of 2-5 mm diameter before starting their first IVF cycle participated in this randomized controlled trial. They were randomized by opening a sealed envelope, receiving either 150 IU (group I, n = 26) or 300 IU (group II, n = 26) of rFSH as a starting dose. The main outcome measures of the study were number of oocytes, poor response (<4 oocytes at retrieval or cancellation due to insufficient follicle growth) and ongoing pregnancy (12 weeks of gestation). RESULTS: The groups were comparable regarding patient characteristics and outcome of the IVF treatment. The median number of oocytes collected was 3 for both groups (P = 0.79). The difference in the mean number of oocytes was 0.3 oocytes in favour of group I (P=0.69). Sixty-five per cent of the patients in group I experienced a poor response and 62% in group II. The ongoing pregnancy rate was 8% in group I and 4% in group II (P = 0.55). CONCLUSIONS: Expected poor response patients, defined as patients with an AFC <5, are likely not to benefit from a higher starting dose of gonadotrophins in IVF.

Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve.

BACKGROUND: The aim of this study was to investigate the predictive accuracy and clinical value of performing either a single or a repeated clomiphene citrate challenge test (CCCT) in predicting poor response in IVF, compared to that of currently used basal ovarian reserve markers. METHODS: Sixty-three patients undergoing their first IVF treatment were prospectively included. After measurement of basal markers on cycle day 3 (cd3) [FSH, inhibin B and antral follicle count (AFC)], a CCCT was performed. FSH and inhibin B levels were measured on day 10 (cd10). A second CCCT was performed after a washout period of one cycle. In all patients the tests were followed by an IVF treatment. Poor response (<4 oocytes or cancellation due to impaired (<3 follicles) or absent follicular growth) was used as primary outcome measure. RESULTS: Both the single as well as the repeated CCCT markers had a rather good discriminative potential for the prediction of poor response (area under the receiver operating characteristic curve (ROCAUC): FSH cd10=0.79, inhibin B cd10=0.79, mean FSH cd10=0.82 and mean inhibin B cd10=0.88). This compared well with the performance of the basal markers (FSH 0.82, inhibin B 0.72 and AFC 0.83). In a multivariate analysis on only the basal variables, FSH cd3 and AFC were selected (ROCAUC 0.89). Only stepwise forward analysis on the repeated CCCT variables revealed a better discriminating potential for the prediction of poor response (ROCAUC 0.92). At a specificity level of approximately 0.97, sensitivity and the positive predictive value were marginally improved in the CCCT models. CONCLUSIONS: Performing a CCCT (single or repeated) has a rather good ability to predict poor response in IVF. However, it appears that the predictive accuracy and clinical value of the CCCT is not clearly better than that of basal FSH in combination with an AFC. Therefore, the use of the CCCT as a predictor of outcome in IVF should not be advocated.

Kinetics of meiosis in azoospermic males: a joint histological and cytological approach.

We have developed a protocol for the identification of aberrant chromosome behavior during human male meiosis up to metaphase of the secondary spermatocyte. Histological evaluation by the Johnsen score of a testicular biopsy was combined with immunofluorescence of first meiotic prophase spermatocytes, using antibodies against synaptonemal complex protein 3 (SYCP3) and the product of the ataxia telangiectasia and rad3-related gene (ATR). This combination enables accurate meiotic prophase substaging and the identification of pachytene spermatocytes with asynapsis. Furthermore, we also investigated the competence of late pachytene primary spermatocytes to complete the first meiotic division up to metaphase and of secondary spermatocytes to transform into metaphase by an in vitro challenge with okadaic acid (OA). We tested this protocol on five males with normal Johnsen scores that presented with obstructive azoospermia, five males with low Johnsen scores and non-obstructive azoospermia and six vasectomized control males of proven fertility and normal Johnsen scores. In all azoospermics, the profiling of meiotic prophase stages by immunofluorescence increases the resolving power of the Johnsen score. In both obstructive and non-obstructive azoospermic patients, relatively more leptotene meiotic prophase stages were counted compared to the controls. In non-obstructive azoospermics, a marked heterogeneity in spermatogenesis was found, after combining the results of all three approaches, pointing at functional mosaicism of the germinal epithelium. Asynaptic pachytene spermatocytes were rarely encountered. Also, when first meiotic metaphase could be induced by OA, chiasma counts were normal. In none of the non-obstructive azoospermic males did the pattern of spermatogenesis resemble that of knock-out mouse azoospermics. We conclude that this combined histological and cytological approach enables a detailed phenotypic classification of infertile males, at a level comparable to that applied for male-sterile knock-out mice with a meiotic defect. This may facilitate the identification of candidate genes for human male infertility.

Towards less confusing terminology in reproductive medicine: a proposal.

The use of the term "infertility" and related terms in reproductive medicine is reviewed. Current terminology is found to be ambiguous, confusing and misleading. We recommend that the fertility investigation report of a couple should consist of statements concerning description, diagnosis and prognosis. The description concerns the duration of non-pregnancy before consulting the clinician. A system for prognostic grading is proposed. The fertility investigation report forms the basis for further action, including the possibility of waiting with treatment in case of almost normal or only slightly reduced fertility. The use of the terms infertility, subfertility and fecundity is not necessary, and it is recommended to avoid them.

Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models.

BACKGROUND: Several models have been published for the prediction of spontaneous pregnancy among subfertile patients. The aim of this study was to broaden the empirical basis for these predictions by making a synthesis of three previously published models. METHODS: We used the original data from the studies of Eimers et al. (1994), Collins et al. (1995) and Snick et al. (1997) on couples consulting for various forms of subfertility. We developed a so-called three-sample synthesis model for predicting spontaneous conception leading to live birth within 1 year after intake based on the three data sets. The predictors used are duration of subfertility, women's age, primary or secondary infertility, percentage of motile sperm, and whether the couple was referred by a general practitioner or by a gynaecologist (referral status). The performance of this model was assessed according to a 'jack-knife' analysis. Because the post-coital test (PCT) was not assessed in one of the samples, a synthesis model including the PCT was based on two samples only. RESULTS: The ability of the synthesis models to distinguish between women who became pregnant and those who did not was comparable to the ability of the one-sample models when applied in the other samples. The reliability of the predictions by the three-sample synthesis model was somewhat better. Predictions improved considerably by including the PCT. CONCLUSIONS: The synthesis models performed better and had a broader empirical basis than the original models. They are therefore better suitable for application in other centres.

Use of stimulated serum estradiol measurements for the prediction of hyperresponse to ovarian stimulation in in vitro fertilization (IVF).

PURPOSE: In ovarian stimulation an exaggerated ovarian response is often seen and is related to medical complications, such as ovarian hyperstimulation syndrome (OHSS), and increased patient discomfort. If it were possible to identify hyperresponders at an early stage of the stimulation phase, adaptation of the stimulation protocol would become feasible to minimize potential complications. Therefore, we studied the usefulness of measuring stimulated serum estradiol (E2) levels in predicting ovarian hyperresponse. METHODS: A total of 109 patients undergoing their first IVF treatment cycle using a long protocol with GnRH agonist was prospectively included. The E2 level was evaluated on day 3 and 5 of the stimulation phase. Two outcome measures were defined. The first was ovarian hyperresponse (collection of > or = 15 oocytes at retrieval and/or peak E2 > 10000 pmol/L, or cancellation due to > or = 30 follicles growing and/or peak E2 > 15000 pmol/L, or OHSS developed). The second outcome measure comprised a subgroup representing the more severe hyperresponders. named extreme-response (cancellation or OHSS developed). RESULTS: The data of 108 patients were analyzed. The predictive accuracy of E2 measured on stimulation day 3 towards ovarian hyperresponse was clearly lower than that of E2 measured on stimulation day 5 (area under the receiver operating characteristic curve (ROCAUC) 0.75 and 0.81, respectively). For extreme-response the predictive accuracy of E2 measured on stimulation day 3 or 5 was comparable (ROCAUC 0.81 and 0.82, respectively). For both outcome measures the stimulated E2 tests yielded only acceptable specificity with moderate sensitivity at higher cutoff levels. Prediction of extreme-response seemed slightly more effective due to a lower error rate. CONCLUSIONS: There is a significant predictive association between E2 levels measured on stimulation day 3 and 5 and both ovarian hyperresponse and extreme-response in IVF. However, the clinical value of stimulated E2 levels for the prediction of hyperresponse is low because of the modest sensitivity and the high false positive rate. For the prediction of extreme-response the clinical value of stimulated E2 levels is moderate.