Antimüllerian hormone as predictor of reproductive outcome in subfertile women with elevated basal follicle-stimulating hormone levels: a follow-up study.

OBJECTIVE: To investigate the role of serum antimüllerian hormone (AMH) as a predictor of live birth and reproductive stage in subfertile women with elevated basal FSH levels. DESIGN: A prospective observational cohort study conducted between February 2005 and June 2009. SETTING: Tertiary fertility center. PATIENT(S): Subfertile women with [1] a regular menstrual cycle (mean cycle length 25-35 days); [2] basal FSH concentrations ≥12.3 IU/L; and [3] younger than 40 years (n = 96). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth and reproductive stage according to the Stages of Reproductive Aging Workshop. RESULT(S): A cumulative live birth rate of 63.5% was observed during a median follow-up of 3.3 years (n = 85). The AMH level was significantly associated with live birth. There was evidence of a nonlinear prediction pattern, with an increase in chances of live birth until an AMH level of 1 µg/L. Other ovarian reserve tests and chronological age appeared of limited value in predicting live birth. In addition, AMH was significantly associated with the timing of reproductive stages (n = 68) (i.e., the occurrence of menopausal transition or menopause during follow-up). CONCLUSION(S): The present findings suggest applicability of AMH determination as a marker for actual fertility in subfertile women with elevated basal FSH levels.

Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause.

The onset of menopause has important implications on women's fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, AMHR2, BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in AMHR2 (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.

Genes involved in initial follicle recruitment may be associated with age at menopause.

CONTEXT: Timing of menopause is largely influenced by genetic factors. Because menopause occurs when the follicle pool in the ovaries has become exhausted, genes involved in primordial follicle recruitment can be considered as candidate genes for timing of menopause. OBJECTIVE: The aim was to study the association of 23 tagging single nucleotide polymorphisms in five genes [Anti-Müllerian hormone (AMH), AMH type II receptor (AMHR2), bone morphogenetic protein 15 (BMP15), forkhead transcription factor L2 (FOXL2), and growth differentiation factor-9 (GDF9)] involved in recruitment of the primary follicle pool, including the AMHR2 gene, which has recently been associated with age at menopause. DESIGN: We conducted a cross-sectional association study. SETTING AND PARTICIPANTS: We studied a population-based sample of 3616 Dutch women with natural menopause. MAIN OUTCOME MEASURE: We measured age at natural menopause. RESULTS: Both studied AMHR2 tagging single nucleotide polymorphisms (rs2002555 and rs11170547) in the AMHR2 gene were associated with age at natural menopause in interaction with parity. Parous rs2002555 G/G carriers had menopause 1 yr later compared with A/A carriers (P = 0.01). For rs11170547, each minor allele (T) was associated with a 0.41-yr later onset of menopause in parous women (P = 0.01). Additionally, rs6521896 in BMP15 was associated with later menopause (ß = 0.41; P = 0.007). Variants in the AMH, FOXL2, and GDF9 genes were not associated with timing of menopause. CONCLUSIONS: The present study confirms an earlier finding that variation in the AMHR2 gene modifies the relation between parity and age at natural menopause. In combination with the association of BMP15 with menopausal age, we find that there is evidence that genes involved in primary follicle recruitment influence timing of menopause.

Human studies on genetics of the age at natural menopause: a systematic review.

BACKGROUND Timing of natural menopause has great implications for fertility and women's health. Age at natural menopause (ANM) is largely influenced by genetic factors. In the past decade, several genetic studies have been conducted to identify genes in ANM, which can help us unravel the biological pathways underlying this trait and the associated infertility and health risks. After providing an overview of the results of the genetic studies performed so far, we give recommendations for future studies in identifying genetic factors involved in determining the variation in timing of natural menopause. METHODS The electronic databases of Pubmed and Embase were systematically searched until September 2009 for genetic studies on ANM, using relevant keywords on the subject. Additional papers identified through hand search were also included. RESULTS Twenty-eight papers emerged from our literature search. A number of genetic regions and variants involved in several possible pathways underlying timing of ANM were identified, including two possible interesting regions (9q21.3 and chromosome 8 at 26 cM) in linkage analyses. Recent genome-wide association studies have identified two genomic regions (19q13.42 and 20p12.3), containing two promising candidate genes (BRKS1 and MCM). In the candidate gene association studies on ANM, very few consistent associations were found. CONCLUSION A number of genetic variants have been discovered in association with ANM, although the overall results have been rather disappointing. We have described possible new strategies for future genetic studies to identify more genetic loci involved in the variation in menopausal age.

Assessment of competence and progressive independence in postgraduate clinical training.

CONTEXT: At present, competency-based, outcome-focused training is gradually replacing more traditional master-apprentice teaching in postgraduate training. This change requires a different approach to the assessment of clinical competence, especially given the decisions that must be made about the level of independence allowed to trainees. METHODS: This study was set within postgraduate obstetrics and gynaecology training in the Netherlands. We carried out seven focus group discussions, four with postgraduate trainees from four training programmes and three with supervisors from three training programmes. During these discussions, we explored current opinions of supervisors and trainees about how to determine when a trainee is competent to perform a clinical procedure and the role of formal assessment in this process. RESULTS: When the focus group recordings were transcribed, coded and discussed, two higher-order themes emerged: factors that determine the level of competence of a trainee in a clinical procedure, and factors that determine the level of independence granted to a trainee or acceptable to a trainee. CONCLUSIONS: From our study, it is evident that both determining the level of competence of a trainee for a certain professional activity and making decisions about the degree of independence entrusted to a trainee are complex, multi-factorial processes, which are not always transparent. Furthermore, competence achieved in a certain clinical procedure does not automatically translate into more independent practice. We discuss the implications of our findings for the assessment of clinical competence and provide suggestions for a transparent assessment structure with explicit attention to progressive independence.