Granulosa-lutein cells from women with anovPCOS are relatively resistant to the effects of insulin-stimulated glucose uptake and utilization compared with those from normal and ovPCO, whilst maintaining normal steroidogenic output in response to physiological doses of insulin. These studies support the probability of a post-receptor, signalling pathway-specific impairment of insulin action in PCOS.

An important scientific breakthrough of the 20th century, IVF helped open new horizons in medicine, such as pre-implantation genetic diagnosis and embryonic stem-cell therapy. A further contribution of assisted reproduction technology has been the better understanding of reproductive ageing. Data from IVF cycles suggest that there is a fixed time-interval between accelerated decline of fertility and the menopause. This leads to the hypothesis that a significant proportion of asymptomatic women in the early thirties may be at risk of early onset of subfertility. IVF provides a model for the development of ovarian reserve tests, some of which appear promising as potential screening tools for early ovarian ageing in the general population.

BACKGROUND Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal–foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls. OBJECTIVE AND RATIONALE The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls. SEARCH METHODS MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger’s test. OUTCOMES Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM. WIDER IMPLICATIONS The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

The female reproductive tract has an active microbiome, and it is suggested that these microbes could influence the outcome of assisted reproductive technologies (ART). This systematic review aimed to assess the vaginal/uterine microbiome, specifically with regard to improving the outcome of ART. English peer-reviewed journals were searched for studies investigating the vaginal/uterine micriobiome and female reproductive tract, using PRISMA guidelines. Twenty-six studies were included, 19 studying the vaginal and seven investigating the uterine microbiome. Studies using culture-based technologies found an abnormal vaginal microbiome AVM was not associated with ART outcome. However, studies using sequence-based technologies found an abnormal vaginal microbiome had a negative effect on ART. An abnormal uterine microbiome impacted ART outcome in all of the studies which used culture-based methods and the most extensive of the two studies using metagenomic sequencing. This review has revealed a lack of translational data relating an abnormal vaginal/uterine microbiome to ART outcomes, with inconsistencies between the results of the different studies. Therefore the nature of the relationship between the vaginal/uterine microbiome and fertility remains unknown. As we better characterize this relationship using modern metagenomic techniques, the potential to manipulate the female reproductive tract microbiome to improve ART could be a reality.

We carried out a controlled retrospective cohort study that showed a strong association between an extremely poor response to ovarian hyperstimulation and early ovarian failure.