F.J. Broekmans

AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis

BACKGROUNDnAnti-Mullerian hormone (AMH) is a marker of ovarian reserve status and represents a good predictor of ovarian response to ovarian hyperstimulation. The aim of this study was to assess the accuracy of AMH and antral follicle count (AFC) as predictors of an excessive response in IVF/ICSI treatment.nnnMETHODSnA systematic review and meta-analysis of the existing literature was performed. Studies were included if 2 × 2 tables for the outcome excessive response in IVF patients in relation to AMH/AFC could be constructed. Using a bivariate meta-analytic model, both summary point estimates for sensitivity and specificity were calculated, as well as summary ROC curves. Clinical value was analysed by calculating post-test probabilities of excessive response at optimal cut-off levels, as well as the corresponding abnormal test rates.nnnRESULTSnNine studies reporting on AMH and five reporting on AFC were found. Summary estimates of sensitivity and specificity for AMH were 82 and 76%, respectively, and 82 and 80%, respectively, for AFC. Comparison of the summary estimates and ROC curves for AMH and AFC showed no statistical difference. Abnormal test rates for AMH and AFC amounted to ∼14 and 16%, respectively, at cut-off levels where test performance is optimal [likelihood ratio for a positive result (LR + ) > 8], with a post-test probability of ± 70%.nnnCONCLUSIONSnBoth AMH and AFC are accurate predictors of excessive response to ovarian hyperstimulation. Moreover, both tests appear to have clinical value. This opens ways to explore the potential of individualized FSH dose regimens based on ovarian reserve testing.

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

CONTEXTnIt 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.nnnOBJECTIVEnThe aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause.nnnDESIGN AND SETTINGnWe conducted a long-term follow-up study at an academic hospital.nnnPARTICIPANTSnA total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria.nnnINTERVENTIONSnAnti-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.nnnMAIN OUTCOME MEASURESnAccuracy 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.nnnRESULTSnA 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.nnnCONCLUSIONSnAMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.

Mild ovarian stimulation for IVF.

BACKGROUNDnMild ovarian stimulation for in vitro fertilization (IVF) aims to achieve cost-effective, patient-friendly regimens which optimize the balance between outcomes and risks of treatment.nnnMETHODSnPubmed and Medline were searched up to end of January 2008 for papers on ovarian stimulation protocols for IVF. Additionally, references to related studies were selected wherever possible.nnnRESULTSnStudies show that mild interference with the decrease in follicle-stimulating hormone levels in the mid-follicular phase was sufficient to override the selection of a single dominant follicle. Gonadotrophin-releasing hormone antagonists compared with agonists reduce length and dosage of gonadotrophin treatment without a significant reduction in the probability of live birth (OR 0.86, 95% CI 0.72-1.02). Mild ovarian stimulation may be achieved with limited gonadotrophins or with alternatives such as anti-estrogens or aromatase inhibitors. Another option is luteinizing hormone or human chorionic gonadotrophin administration during the late follicular phase. Studies regarding these approaches are discussed individually; small sample size of single studies along with heterogeneity in patient inclusion criteria as well as outcomes analysed does not allow a meta-analysis to be performed. Additionally, the implications of mild ovarian stimulation for embryo quality, endometrial receptivity, cost and the psychological impact of IVF treatment are discussed.nnnCONCLUSIONSnEvidence in favour of mild ovarian stimulation for IVF is accumulating in recent literature. However, further, sufficiently powered prospective studies applying novel mild treatment regimens are required and structured reporting of the incidence and severity of complications, the number of treatment days, medication used, cost, patient discomfort and number of patient drop-outs in studies on IVF is encouraged.

The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF

BACKGROUNDnMilder ovarian stimulation protocols for in vitro fertilization (IVF) are being developed to minimize adverse effects. Mild stimulation regimens result in a decreased number of oocytes at retrieval. After conventional ovarian stimulation for IVF, a low number of oocytes are believed to represent poor ovarian reserve resulting in reduced success rates. Recent studies suggest that a similar response following mild stimulation is associated with better outcomes.nnnMETHODSnThis review investigates whether the retrieval of a low number of oocytes following mild ovarian stimulation is associated with impaired implantation rates. Three randomized controlled trials comparing the efficacy of the mild ovarian stimulation regimen (involving midfollicular phase initiation of FSH and GnRH co-treatment) for IVF with a conventional long GnRH agonist co-treatment stimulation protocol could be identified by means of a systematic literature search.nnnRESULTSnThese studies comprised a total of 592 first treatment cycles. Individual patient data analysis showed that the mild stimulation protocol results in a significant reduction of retrieved oocytes compared with conventional ovarian stimulation (median 6 versus 9, respectively, P < 0.001). Optimal embryo implantation rates were observed with 5 oocytes retrieved following mild stimulation (31%) versus 10 oocytes following conventional stimulation (29%) (P = 0.045).nnnCONCLUSIONSnThe optimal number of retrieved oocytes depends on the ovarian stimulation regimen. After mild ovarian stimulation, a modest number of oocytes is associated with optimal implantation rates and does not reflect a poor ovarian response. Therefore, the fear of reducing the number of oocytes retrieved following mild ovarian stimulation appears to be unjustified.

Testing ovarian reserve to predict age at menopause

In modern society with women delaying pregnancy, predicting the age of the natural menopause with its preceding infertility will allow making informed choices about when to try starting to have children. Also if premature menopause could be predicted in young women, strategies could be instigated to reduce the long term health risks of early estrogen deficiency. This review examines the physiology of ovarian ageing, with the menopause being the final outcome. Long and short term predictive markers of the age of the menopause and the preceding natural infertility are evaluated. Many subtle changes in the endocrine regulation of ovarian function with advancing age may seem interesting but currently are not clinically useful as a predictive test. Examples are changes in concentrations of estradiol, progesterone, luteinizing hormone (LH) and activin, as well as follicle dynamics. Other features hold more promise. Among these are chronological age, family history, anti-Müllerian hormone (AMH), poor response to in vitro fertilization (IVF), basal follicle-stimulating hormone (FSH) and the antral follicle count for long term prediction. For short term prediction, cycle shortening and occurrence of vasomotor symptoms may prove useful. To date, none of these markers has been found to have sufficient predictive accuracy in individual women. Results of new and ongoing longitudinal studies may provide better predictive models. In particular, use of genetic profiles may add to the accuracy of currently known markers.

Reproductive and Lifestyle Determinants of Anti-Müllerian Hormone in a Large Population-based Study

CONTEXTnAnti-müllerian hormone (AMH) is an ovarian reserve marker that is increasingly applied in clinical practice as a prognostic and diagnostic tool. Despite increased use of AMH in clinical practice, large-scale studies addressing the influence of possible determinants on AMH levels are scarce.nnnOBJECTIVEnWe aimed to address the role of reproductive and lifestyle determinants of AMH in a large population-based cohort of women.nnnDESIGNnIn this cross-sectional study, age-specific AMH percentiles were calculated using general linear modeling with CG-LMS (Cole and Green, Lambda, Mu, and Sigma model, an established method to calculate growth curves for children).nnnSETTINGnWomen from the general community participating in the Doetinchem Cohort study were assessed.nnnPARTICIPANTSnTwo thousand three hundred twenty premenopausal women were included.nnnMAIN OUTCOME MEASUREnThe effect of female reproductive and lifestyle factors on shifts in age-specific AMH percentiles was studied.nnnRESULTSnIn comparison to women with a regular menstrual cycle, current oral contraceptive (OC) users, women with menstrual cycle irregularity, and pregnant women had significantly lower age-specific AMH percentiles (for OC use, 11 percentiles lower; for cycle irregularity, 11 percentiles lower; and for pregnancy, 17 percentiles lower [P value for all <.0001]). Age at menarche and age at first childbirth were not associated with the age-specific AMH percentile. Higher parity was associated with 2 percentiles higher age-specific AMH (P = .02). Of the lifestyle factors investigated, current smoking was associated with 4 percentiles lower age-specific AMH percentiles (P = .02), irrespective of the smoking dose. Body mass index, waist circumference, alcohol consumption, physical exercise, and socioeconomic status were not significantly associated with age-specific AMH percentiles.nnnCONCLUSIONSnThis study demonstrates that several reproductive and lifestyle factors are associated with age-specific AMH levels. The lower AMH levels associated with OC use and smoking seem reversible, as effects were confined to current use of OC or cigarettes. It is important to give careful consideration to the effect of such determinants when interpreting AMH in a clinical setting and basing patient management on AMH.

Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis

OBJECTIVEnTo evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups.nnnDESIGNnAuthors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy.nnnSETTINGnInxa0vitro fertilization clinics.nnnPATIENT(S)nA total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nExcessive response prediction.nnnRESULT(S)nWe included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same.nnnCONCLUSION(S)nWe demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age.

Clinical outcomes in relation to the daily dose of recombinant follicle-stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis

BACKGROUNDnThe optimal ovarian stimulation dose to obtain the best balance between the probability of pregnancy and the risk of complications, while maximizing cost-effectiveness of in vitro fertilization (IVF) treatment, is yet to be established.nnnMETHODSnA systematic search of the electronic databases PubMed, EMBASE and Cochrane library, from 1984 until October 2009 for randomized controlled trials comparing different doses of recombinant FSH in IVF, was performed.nnnRESULTSnTen studies (totaling 1952 IVF cycles) were included in the present meta-analysis, comprising patients younger than 39 years with regular menstrual cycle, normal basal FSH levels and two normal ovaries. Comparison was made between studies using a daily dose of 100 versus 200 IU recFSH, and between 150 versus 200 IU recFSH or higher. Although oocyte yield was greater in the >200 IU/day dose group, pregnancy rates were similar compared with lower dose groups. The risk of insufficient response to ovarian stimulation was greatest in the 100 IU/day dose group. The risk of developing ovarian hyperstimulation syndrome was greater in the >200 IU/day dose group. The number of embryos available for cryopreservation was lowest in the 100 IU/day group, but similar comparing the 150 IU/day and the >200 IU/day dose groups.nnnCONCLUSIONSnThis meta-analysis suggests that the optimal daily recFSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy and embryo cryopreservation rates. Furthermore, the wide spread adherence to this optimal dose will allow for a considerable reduction in IVF costs and complications.

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.

Serum AMH Levels in Women With a History of Preeclampsia Suggest a Role for Vascular Factors in Ovarian Aging

CONTEXTnThe association between early menopause and vascular disease as a possible causative factor has recently received attention. Preeclampsia (PE) is associated with future cardiovascular risk factors, and this premature vascular aging potentially modifies the ovarian aging process.nnnOBJECTIVEnThe purpose of this study was to assess whether women with a history of PE have lower anti-Müllerian hormone (AMH) levels than women with normotensive pregnancies.nnnDESIGNnThis was a retrospective cohort study.nnnSETTINGnThe study was conducted in a tertiary referral center.nnnPATIENTSnClinical data and blood samples of participants in the Preeclampsia Risk EValuation in FEMales study were used (336 women with a history of PE and 329 women after a normotensive pregnancy).nnnINTERVENTIONSnThere were no interventions.nnnMAIN OUTCOME MEASURESnThe relative decrease in AMH levels was assessed after a median follow-up of 10.5 years.nnnRESULTSnThe mean AMH level was 2.00 ± 1.87 μg/L in the PE group compared with 2.26 ± 2.56 μg/L in the reference group. Linear regression analysis with censoring for undetectable AMH levels, adjusted for age, smoking, and hormonal contraceptive use, showed a relative reduction in AMH levels of 20.9% at any age (fold change 0.79, 95% confidence interval, 0.67-0.94).nnnCONCLUSIONSnWe demonstrate that women with a history of PE have significantly lower AMH levels than women with normotensive pregnancies. Calculations based on a reference population indicate advancement of reproductive age of approximately 1.5 years. Because PE is considered a manifestation of impaired vascular health, these results support the hypothesis that compromised vascular health could act as a causative mechanism in early ovarian aging.