Tom Kelsey

Human ovarian reserve from conception to the menopause.

The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50–51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve ( = 0.81). When restricted to ages up to 25 years, the ADC curve has  = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.

Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection.

Anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells (GC) of the developing pre-antral and antral follicles, and AMH is increasingly used to assess ovarian function. It is unclear which size follicles make the most AMH (total content) and are the main contributors to circulating AMH concentrations. To determine AMH gene expression in GC (q-RT-PCR) and follicular AMH production (Elisa and RIA) in relation to follicular development, 87 follicles (3-13 mm diameter) including both GC and the corresponding follicular fluid (FF) were collected in connection with fertility preservation of human ovaries. Further, follicle number and diameter, graded in 1 mm increments, were determined by 3D ultrasound in 113 women in their natural menstrual cycle to determine follicle number and diameter in relation to circulating AMH levels. This study demonstrates for the first time a positive association between AMH gene expression in human and both total follicular fluid AMH (P < 0.02) and follicular fluid AMH concentration (P < 0.01). AMH gene expression and total AMH protein increased until a follicular diameter of 8 mm, after which a sharp decline occurred. In vivo modelling confirmed that 5-8 mm follicles make the greatest contribution to serum AMH, estimated for the first time in human to be 60% of the circulating concentration. Significant positive associations between gene expression of AMH and FSHR, AR and AMHR2 expression (P < 0.00001 for all three) and significant negative association between follicular fluid AMH concentration and CYP19a1 expression were found (P < 0.0001). Both AMH gene expression (P < 0.02) and follicular fluid concentration of AMH (P < 0.00001) correlated negatively with estradiol concentration.

Can anti-mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data

CONTEXT Existing biochemical tests for polycystic ovary syndrome (PCOS) have poor sensitivity and specificity. Many women with PCOS have high anti-Müllerian hormone (AMH) concentrations; thus, this may be a useful addition to the diagnostic criteria. OBJECTIVE A systematic literature review was performed to assess the true accuracy of AMH in the prediction of PCOS and to determine the optimal diagnostic threshold. DATA SOURCES Published and gray literature were searched for all years until January 2013. STUDY SELECTION Observational studies defining PCOS according to the Rotterdam criteria and assessing the value of AMH in diagnosing PCOS were selected. Ten studies of the initial 314 hits reporting AMH values in the diagnosis of PCOS were included in the meta-analysis and the construction of the summary receiver-operating characteristic curve. Four studies that plotted individual AMH serum levels of women with PCOS and controls on graphs were selected for individual data extraction. DATA EXTRACTION Two researchers independently assessed the abstracts resulted from the initial search against the inclusion criteria, graded the papers for selection and verification biases, and selected the papers that assessed the value of AMH in diagnosing PCOS. Data were extracted from 4 studies with the plotted individual data on graphs with the help of computer software. DATA SYNTHESIS The meta-analysis of the extracted data demonstrated the specificity and sensitivity in diagnosing PCOS in the symptomatic women of 79.4% and 82.8%, respectively, for a cutoff value of AMH of 4.7 ng/mL. The area under the curve was 0.87 (95% confidence interval 0.83-0.92), identical with the area under the curve of 0.87 for the summary receiver-operating characteristic curve involving 10 separate studies. CONCLUSIONS AMH may be a useful initial diagnostic test for PCOS subject to validation in prospective population cohorts.

The predictive accuracy of anti-Müllerian hormone for live birth after assisted conception: a systematic review and meta-analysis of the literature

BACKGROUND Anti-Müllerian hormone (AMH) is an established marker of ovarian reserve and a good predictor of poor or excessive ovarian response after controlled hyperstimulation. However, it is unclear whether it can predict the ultimate outcome of assisted conception, live birth. We undertook a systematic review and meta-analysis to examine whether AMH is a predictor of live birth in women undergoing assisted conception. METHODS The study was conducted according to the PRISMA guidelines. PubMed, Embase, Medline, Web of Knowledge and the Cochrane trial register and unpublished literature were searched. Studies fulfilling the eligibility criteria were included in the systematic review and those with extractable data were included in the meta-analysis. Quality assessment was performed with the QUADAS 2 checklist. A summary estimate of diagnostic odds ratio (DOR) was derived using the random effects model for binary data. A hierarchical summary receiver operating characteristic model provided pooled estimates before and after adjusting for age and AMH assay as covariates. RESULTS Out of 361 non-duplicate studies, 47 were selected; 17 met the eligibility criteria and 13 had extractable data and thus were included in the meta-analysis. Three out of the 13 studies included only women with expected low ovarian reserve and were analysed individually from the remaining 10 to minimize heterogeneity. The DOR for women with unknown ovarian reserve (n = 5764 women) was 2.39 (95% confidence interval (CI): 1.85-3.08). After adjustment for age the DOR was little changed at 2.48 (95% CI: 1.81-3.22) and the DOR adjusted for AMH assay was almost identical at 2.42 (95% CI: 1.86-3.14). For women with expected low ovarian reserve (n = 542 women) the DOR was 4.63 (95% CI: 2.75-7.81). CONCLUSIONS AMH, independently of age, has some association with predicting live birth after assisted conception and may be helpful when counselling couples before undergoing fertility treatment. However, its predictive accuracy is poor.

Groups and Constraints: Symmetry Breaking during Search

We present an interface between the ECLiPSe constraint logic programming system and the GAP computational abstract algebra system. The interface provides a method for efficiently dealing with large numbers of symmetries of constraint satisfaction problems for minimal programming effort. We also report an implementation of SBDS using the GAP-ECLiPSe interface which is capable of handling many more symmetries than previous implementations and provides improved search performance for symmetric constraint satisfaction problems.

Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation

Summary Background Ovarian tissue cryopreservation with later reimplantation has been shown to preserve fertility in adult women, but this approach remains unproven and experimental in children and adolescents. We aimed to assess the use of the Edinburgh selection criteria for ovarian tissue cryopreservation in girls and young women with cancer to determine whether we are offering this invasive procedure to the patients who are most at risk of premature ovarian insufficiency. Methods Cryopreservation of ovarian tissue has been selectively offered to girls and young women with cancer who met the Edinburgh selection criteria since 1996. Between Jan 1, 1996, and June 30, 2012, 410 female patients younger than 18 years at diagnosis were treated for cancer (including leukaemia and brain tumours) at the Edinburgh Childrens Cancer Centre, which serves the whole South East of Scotland region. We determined the ovarian status of these patients from review of clinical records and classified them as having premature ovarian insufficiency or not, or as unable to be determined. Patients younger than 12 years at time of data cutoff (Jan 31, 2013) were excluded from the analysis. Findings 34 (8%) of the 410 patients met the Edinburgh selection criteria and were offered ovarian tissue cryopreservation before starting cancer treatment. 13 patients declined the procedure and 21 consented, and the procedure was completed successfully in 20 patients. Of the 20 patients who had ovarian tissue successfully cryopreserved, 14 were available for assessment of ovarian function. Of the 13 patients who had declined the procedure, six were available for assessment of ovarian function. Median age at the time of follow-up for the 20 assessable patients was 16·9 years (IQR 15·5–21·8). Of the 14 assessable patients who had successfully undergone ovarian cryopreservation, six had developed premature ovarian insufficiency at a median age of 13·4 years (IQR 12·5–14·6), one of whom also had a natural pregnancy. Of the six assessable patients who had declined the procedure, one had developed premature ovarian insufficiency. Assessment of ovarian function was possible for 141 of the 376 patients who were not offered cryopreservation; one of these patients had developed premature ovarian insufficiency. The cumulative probability of developing premature ovarian insufficiency after treatment was completed was significantly higher for patients who met the criteria for ovarian tissue cryopreservation than for those who did not (15-year probability 35% [95% CI 10–53] vs 1% [0–2]; p<0·0001; hazard ratio 56·8 [95% CI 6·2–521·6] at 10 years). Interpretation The results of this analysis show that the Edinburgh selection criteria accurately identify the few girls and young women who will develop premature ovarian insufficiency, and validate their use for selection of patients for ovarian tissue cryopreservation. Further follow-up of this cohort of patients is likely to allow refinement of the criteria for this experimental procedure in girls and young women with cancer. Funding UK Medical Research Council.

Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults

Preservation of gonadal function is an important priority for the long-term health of cancer survivors of both sexes and all ages at treatment. Loss of opportunity for fertility is a prime concern in both male and female cancer survivors, but endocrine effects of gonadal damage are likewise central to long-term health and wellbeing. Some fertility preservation techniques, such as semen and embryo cryopreservation, are established and successful in adults, and development of oocyte vitrification has greatly improved the potential to cryopreserve unfertilised oocytes. Despite being recommended for all pubertal male patients, sperm banking is not universally practised in paediatric oncology centres, and very few adolescent-friendly facilities exist. All approaches to fertility preservation have specific challenges in children and teenagers, including ethical, practical, and scientific issues. For young women, cryopreservation of ovarian cortical tissue with later replacement has resulted in at least 40 livebirths, but is still regarded as experimental in most countries. For prepubertal boys, testicular biopsy cryopreservation is offered in some centres, but how that tissue might be used in the future is unclear, and so far no evidence suggests that fertility can be restored. For both sexes, these approaches involve an invasive procedure and have an uncertain risk of tissue contamination in haematological and other malignancies. Decision making for all these approaches needs assessment of the individuals risk of fertility loss, and is made at a time of emotional distress. Development of this specialty needs better provision of information for patients and their medical teams, and improvements in service provision, to match technical and scientific advances.

Data-driven assessment of the human ovarian reserve

Human ovarian physiology is still poorly understood, with the factors and mechanisms that control initiation of follicular recruitment and loss remaining particularly unclear. Conventional hypothesis-led studies provide new data, results and insights, but datasets from individual studies are often small, allowing only limited interpretation. Great power is afforded by the aggregation of data from multiple studies into single datasets. In this paper, we describe how modern computational analysis of these datasets provides important new insights into ovarian function and has generated hypotheses that are testable in the laboratory. Specifically, we can hypothesize that age is the most important factor for variations in individual ovarian non-growing follicle (NGF) populations, that anti-Müllerian hormone (AMH) levels generally rise and fall in childhood years before peaking in the mid-twenties, and that there are strong correlations between AMH levels and both NGF populations and rates of recruitment towards maturation, for age ranges before and after peak AMH levels.

External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients

The value of anti-müllerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts.This study reports the external validation of a quadratic model-based AMH–age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH–age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations.