Evaluating the influence of progesterone concentration and time of exposure on in vitro endometrial decidualisation

This study aimed to evaluate the influence of progesterone (concentration and time of exposure) on endometrial decidualisation using an in vitro model cell line: Human Endometrial Stromal Cells (HESCs). HESCs exposed to progesterone (1 and 10 μM) had higher percentages of decidualised cells and higher expression of the decidual marker (Insulin Like Growth Factor Binding Protein 1 (IGFBP1)) compared with those exposed to (0.1 μM). Among those HESCs cultured with 1 μM progesterone for 11 days, the highest rate of morphological differentiation (40–50%) occurred between days 7–9 and IGFBP1 peaked on day 7. The cell-cycle pathway was significantly down-regulated in HESCs exposed to at least 1 μM progesterone regardless of the incubation period. We conclude that exposure to high progesterone concentration for 7–9 days is essential to maximise the process of decidualisation

Suboptimal mid-luteal progesterone concentrations are associated with aberrant endometrial gene expression, potentially resulting in implantation failure

Research questionWhat is the difference in endometrial transcriptomics between women with normal and with low mid-luteal progesterone during the implantation window?DesignAn endometrial biopsy and serum progesterone concentration were taken from participants during the mid-luteal phase (LH+7 to LH+9). A total of 12 participants were recruited and categorized into two groups based on their progesterone concentrations: normal progesterone (>15 ng/ml, n = 6) and low progesterone ([less than] 15 ng/ml, n = 6). Global endometrial gene expression between the two groups was compared by microarray techniques. Principal component analysis was used to display the gene's expression pattern. Pathway and gene ontology enrichment analysis were performed to determine the biological mechanism of progesterone on the endometrium.ResultsSeveral key genes related to endometrial receptivity were found to be regulated by progesterone. With regard to gene ontology and pathway analysis, progesterone was shown to be mainly involved in structure morphogenesis predominantly during a process of decidualization, extracellular matrix–receptor interaction and cell adhesion. Distinct differences were observed in the transcriptomic profiles between the two groups, indicating potential impairment of endometrial receptivity in women with suboptimal progesterone concentrations. There was a relatively similar pattern of gene expression between endometrial samples with progesterone concentrations approximately 10 ng/ml and >15 ng/ml. Thus, a progesterone concentration of between 10 and 15 ng/ml appears to be sufficient to induce endometrial receptivity.ConclusionsAbnormally low progesterone below the threshold of 10–15 ng/ml during the implantation window results in aberrant endometrial gene expression that may affect implantation potential

Diagnosis of Congenital Uterine Abnormalities: Practical Considerations

As most congenital uterine abnormalities are asymptomatic, the majority of them are detected incidentally. While most women with uterine anomalies have a normal reproductive outcome, some may experience adverse reproductive outcomes. Accurate diagnosis and correct classification help in the appropriate counselling of women about their potential reproductive prognosis and risks and for planning any intervention. Evaluation of the internal and external contours of the uterus is the key in making a diagnosis and correctly classifying a uterine anomaly. Considering this, the gold standard test has been the combined laparoscopy and hysteroscopy historically, albeit invasive. However, 3D ultrasound has now become the diagnostic modality of choice for uterine anomalies due to its high degree of diagnostic accuracy, less invasive nature and it being comparatively less expensive. While 2D ultrasound and HSG are adequate for screening for uterine anomalies, MRI and combined laparoscopy and hysteroscopy are reserved for diagnosing complex Mullerian anomalies. Imaging for renal anomalies is recommended if a uterine anomaly is diagnosed

The prevalence of hyperprolactinaemia in subfertile ovulatory women and its impact on fertility treatment outcome

Subtle hyperprolactinaemia is not an uncommon finding in ovulatory subfertile women. The objective of this study is to evaluate the prevalence of hyperprolactinaemia in subfertile ovulatory and oligo-anovulatory women, and to determine if hyperprolactinaemia influences fertility treatment outcome. All women (n = 1010) who attended the fertility clinic of a UK tertiary hospital during 2015–2019 were included. Out of 804 eligible women analysed, 575 women (71.5%) were ovulatory and 229 (28.5%) were oligo-anovulatory. Prevalence of hyperprolactinaemia was higher in the ovulatory group than in the oligo-anovulatory group (26.8% vs. 14.4%; OR: 2.2; 95% confidence interval (CI): 1.4–3.2). On sub-group analysis, the prevalence of mild, moderate and severe hyperprolactinaemia was 23.0%, 3.7% and 0.2% in ovulatory women and 11.8%, 1.7% and 0.9% in oligo-anovulatory women. Mild hyperprolactinaemia was found to be more prevalent in the ovulatory group (OR: 2.2; 95%CI: 1.4–3.5). Ongoing pregnancy/livebirth rates were similar between hyperprolactinaemic and normoprolactinaemic women (42.8% vs. 46.7%). Hyperprolactinaemia did not have an impact on ongoing pregnancy/livebirth rates in both ovulatory and oligo-anovulatory women (OR:0.8; 95%CI: 0.5–1.1; OR: 1.2; 95%CI: 0.6–2.5, respectively). Hyperprolactinaemia is prevalent among ovulatory women, although most had mildly raised clinically insignificant levels. Elevated prolactin levels in ovulatory women do not seem to impact on pregnancy outcome. Impact Statement What is already known on this subject? Prolactin has been linked to ovulation and fertility. Prolactin testing is not generally recommended for subfertile women with regular menstrual cycles, which is a surrogate marker of ovulation. However, some clinicians, particularly in the general practice, still perform prolactin test as part of baseline endocrine profile. What do the results of this study add? Prevalence of hyperprolactinaemia in subfertile ovulatory women was 26.8% (154/575), of which 86% (132/154) were mild. Further, the livebirth/ongoing pregnancy rates were similar between hyperprolactinaemic and normoprolactinaemic women. Prolactin being a sensitive hormone, responsive to even minimal stress and its high levels not influencing clinical pregnancy outcome, prolactin measurement is not needed in women having regular menstrual cycles. What are the implications of these findings for clinical practice and/or further research? Hyperprolactinaemia was not uncommon in ovulatory women, although most had mildly elevated levels. Hyperprolactinaemia did not have any impact on fertility treatment outcome. Serum prolactin should not be tested in ovulating women, as mild elevations are commonly present and have no clinical significance

Aetiology of recurrent miscarriage and the role of adjuvant treatment in its management: a retrospective cohort review

We conducted a retrospective review into the role of commonly prescribed conventional adjuvant treatments in improving live birth rates after recurrent miscarriage (RM). Data from 301 couples attending the RM clinic in two Tertiary teaching hospitals were analysed with their live birth rate following a further pregnancy and a prevalence of conditions investigated in RM being the main outcomes measured. We found that 26% of women had explained RM and 74% had unexplained RM. Adjuvant versus conservative management did not improve the live birth rates in those with unexplained RM (68.4% vs. 76.6%, respectively; p = .28). The prevalence of anti-phospholipid syndrome, inherited thrombophilia, thyroid disease, parental karyotype abnormalities and structural uterine abnormalities were 7.4%, 4.5%, 6.6%, 2.9% and 6.6%, respectively. In conclusion, empirical adjuvant treatment for the management of women with unexplained RM does not appear to offer any benefit as they have a good prognosis with early pregnancy support alone.Impact statement What is already known on this subject? Does the adjuvant treatment in the management of unexplained recurrent miscarriage (RM) improve successful pregnancy outcomes? High-quality data regarding the management and outcomes of RM is very limited, with many clinicians prescribing adjuvant treatments for unexplained RM with very little good quality evidence of their benefit or risk. What do the results of this study add? We carried out a retrospective cohort study of all patients attending a recurrent miscarriage clinic over a two-year period at specialist clinics in two tertiary referral centres to evaluate the prevalence of associated diseases, the treatments given and the outcomes in subsequent pregnancies. This study will help clinicians counsel their patients about management options in RM and help them reassure their patients that the prognosis with conservative management alone is good. This will help to avoid any unnecessary use of adjuvant treatment and its associated risks and cost. What are the implications of these findings for clinical practice and/or further research? This study demonstrates that adjuvant treatments in unexplained RM have no significant benefit on future live birth rates. Despite this finding, high quality, prospective, randomised controlled trials looking at both adverse outcomes and benefits of adjuvant treatment in RM are needed

Frozen Blastocyst Embryo Transfer: Comparison of Protocols and Factors Influencing Outcome

Background: Various factors, including treatment protocols, can influence the outcomes of frozen embryo transfers (FETs). The study objectives were to compare different endometrial preparation protocols of FET cycles and to evaluate the factors, including the endometrial thickness (ET), that affect outcomes. Methods: This observational cohort study involved 5037 women undergoing FETs at eight tertiary clinics in the UK between January 2016 and March 2019. The endometrial preparation protocols used were natural cycle (NC-FETs), artificial hormone support cycle with oestradiol valerate but without pituitary downregulation (AC-FETs) and artificial hormone support cycle with agonist downregulation (ACDR-FETs). Results: The mean (±SD) ages across NC-FET, AC-FET and ACDR-FET groups were 36.5 (±4.2), 35.9 (±5.0) and 36.4(±4.9) years, respectively. LBRs were comparable (40.7%, 175/430; 36.8%, 986/2658; and 36.7%, 716/1949, respectively) across the three groups. Clinical pregnancy, implantation, multiple pregnancies, miscarriage and ectopic pregnancy rates were also similar. In the regression analysis of variables including age, duration of infertility, number of embryos transferred, protocol type and endometrial thickness, age was the only significant predictor of LBRs, although its predictive ability was poor (AUC: 0.55). With the overall LBR of the study population being 37.1%, the post-test probability of a live birth at an ET of <5 mm was 0%, and at 5–5.9, 6–6.9, 7–7.9 and 8–8.9 mm, the probabilities were 16.7%, 33.8%, 36.7% and 37.7%, respectively. The LBR remained above 35% up to the 14–14.9 mm range and then declined gradually to 23% for the 17–25 mm range. Conclusions: The FET outcomes were similar for the three protocols used for endometrial preparation. The protocol type and endometrial thickness were not predictive of FET outcomes; age was the only predictive variable, despite its low predictive ability

Odds and Predictors of Monozygotic Twinning in a Multicentre Cohort of 25,794 IVF Cycles

The rate of monozygotic twinning (MZT) has seen a gradual increase in recent years. Numerous parameters involved in ART procedures are blamed for this surge, even though the exact explanation is as yet unknown. Our study’s objectives were to determine the risk variables for monozygotic twinning after ART and to estimate their prevalence. We examined 25,794 IVF cycles for the incidence of monozygotic twinning in this observational analysis. Our study, which was carried out across seven tertiary IVF centres over the course of four years, found an overall MZT rate of 0.37% per embryo transfer procedure and 0.88% of all pregnancies. Monozygotic twinning was more commonly seen in fresh single-embryo transfer (SET) and blastocyst transfer cycles. Larger multicentre studies are needed to explore the potential risk variables

Global inequality in sub-fertility treatment needs safer, cost effective, evidence-based and economically viable choices for patients and stakeholders

The global increase in subfertility diagnosis and treatments and the rise of private equity investors concentrating on high profits based on in vitro fertilisation (IVF) treatments raise profound societal and economic questions for stakeholders and patients. The question remains whose benefits will ultimately be greater when promoting high margins treatment options resulting from cross-border mergers and acquisitions of IVF clinics? This paper covers wide-ranging issues from the erroneously constructed UK National Institute for Health and Care Excellence’s (NICE) guidelines on treatment choices, the cost-effectiveness of treatments, the promotion of IVF, and add-ons where evidence remains minimal, the commercial size of the fertility industry. Investment in improving intrauterine insemination (IUI) success rates has understandably been avoided for its short-term impact on the IVF industry. However, IUI efficiency would cut across many of the global subfertility treatment economic and access problems while allowing stakeholder, fee-paying, and patients financial savings will likely allow for more funded IVF cycles in acutely deserving cases. The recommendations will help expand choices for globally economically challenged patients' and services while enhancing an ethical and moral dimension towards fertility treatment choices for patients and stakeholders

Letter: Cost-effectiveness analyses in ART consumerism require transparency, simplicity and reproducibility

No abstract available