الفهرس 
Acknowledgements
Human endometrium and its receptivityOnly 14 pages are availabe for public view
 |  | from | 112 |  |  |
| | | from | 112 | | |
Abstract
In the present thesis we conducted an observational clinical study and a systematic review and meta-analysis.
The cross-sectional observational study was conducted between January 2018 to April 2019 in Women’s Health Hospital, Department of Obstetrics and Gynecology, Faculty of medicine, Assiut University, Egypt.
Ninety participants were included and divided into3 groups:
group 1: 30 women with unexplained infertility
group 2: 30 women with PCOS
Group3: 30 healthy fertile women as a control group
The aim was to assess endometrial thickness, 2D Pulsed wave Doppler of uterine arteries, endometrial volume, uterine volume and 3D Power Doppler of endometrium and sub-endometrium in women with unexplained infertility and in women with PCOS compared to the control group of healthy fertile women.
In the systematic review and a meta-analysis we aimed to compare the impact of CC versus other drug regimens on mid-cycle endometrial thickness, ovulation, pregnancy and live birth rates in women with WHO group II ovulatory disorders (PCOS).
MEDLINE, EMBASE, Scopus, Web of Science, The Cochrane Central Register of Clinical Trial (CENTRAL), and the non-MEDLINE subset of PubMed were searched from inception to December 2016 and cross-checked references of relevant articles. We only included randomized controlled trials (RCTs). Outcomes were mid-cycle endometrial thickness, ovulation, pregnancy and live birth rates. We pooled weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous variables (EMT) and risk ratios (RR) with 95% CI for binary variables (ovulation, pregnancy and live birth rates).
• Summary of key findings
Endometrial thickness:
Although endometrial thickness measured at its thickest part in the mid-sagittal plane during the mid-luteal phase was lower in women with unexplained infertility than other groups, there was no statistically significant difference between all groups of the study.
Endometrial and uterine volume:
There was no significant difference in both endometrial and uterine volumes between all groups of the study
Pulsed wave Doppler indices (PI, RI) of both uterine arteries:
Both pulsatility and resistance indices of both uterine arteries did not differ statistically across the included groups.
Endometrial blood perfusion:
Using 3D Power Doppler, quantitative assessment of endometrial blood flow was expressed as VI, FI and VFI. Endometrial perfusion was significantly lower in women with unexplained infertility than other groups.
Also endometrial perfusion was significantly lower in women with PCOS than women in control group.
Sub-endometrial blood flow:
Using 3D Power Doppler, quantitative assessment of sub-endometrial blood flow was expressed as VI, FI and VFI. Sub-endometrial perfusion was significantly lower in women with unexplained infertility than control group.
In women with PCOS, all indices of sub-endometrial perfusion were lower than control group except VI.
Correlation between women’s BMI and ultrasonographic measurements:
A non-statistically significant negative correlation between women’s BMI and each of the following ultrasonographic measurements respectively (uterine volume and 3D Power Doppler indices (VI, FI and VFI) of endometrium and sub-endometrium in women with PCOS.
Correlation of endometrial thickness, perfusion and sub-endometrial perfusion:
There was no correlation between endometrial thickness and endometrial and sub-endometrial perfusion in women with unexplained infertility and PCOS.
Main findings of the present systematic review and meta-analysis:
The present systematic review and meta-analysis on the effect of CC and other ovulation induction drugs in infertile women with WHO group II anovulation showed that CC resulted in lower endometrial thickness and lower pregnancy and live birth rates than letrozole for comparable ovulation rates.
When compared to NO donors or NAC, CC resulted in lower endometrial thickness, and lower ovulation and pregnancy rates, but the number of studies on these comparisons was limited.
The overall quality of evidence in the main comparison between CC and letrozole was rated as very low.
• Strengths and limitations
In the present clinical study we included three groups of women; unexplained infertility, PCOS and control group. We aimed to investigate the uterine perfusion using a relatively recent technique; 3D Power Doppler in different types of infertility and compare to a control group of healthy fertile group. Such design would assess the possible individual role of endometrial and sub-endometrial perfusion in different types of infertility.
Another strength in the present study was that we investigated the intra-observer reliability of 3D ultrasound indices (endometrial volume, endometrial and sub-endometrial VI, FI and VFI) in 15 participants (five in each group) through calculation of the intra-class correlation coefficient (ICC) and 95% confidence interval using a one-way random effects model. We found that ICC was higher than 0.75 which indicates good intra-observer reliability.
However the present clinical study had limitations. We included women with PCOS who fulfilled Rotterdam ASRM/ESHRE criteria (112), but we did not stratify them according to different phenotypic variation. In 2012, NIH Experts Panel recommended the maintenance of the broad diagnostic criteria of Rotterdam, but focused on the need for specific identification of the phenotype of each patient (88). By using the possible combinations of these criteria, four different phenotypes of PCOS were identified: i) hyperandrogenism (clinical or biochemical) and chronic anovulation; ii) hyperandrogenism and polycystic ovaries on ultrasound but with ovulatory cycles; iii) chronic anovulation and polycystic ovaries without hyperandrogenism; and, finally, iv) hyperandrogenism, chronic anovulation and polycystic ovaries (88). This overall inclusion might have masked the presence of a possible difference in uterine perfusion in different clinical and biochemical variants of PCOS.
Another limitation of the present clinical study was that it was of a cross sectional type so we did not follow up patients until pregnancy if occurred. This would have been beneficial especially in unexplained infertility group managed expectantly because we could have compared uterine perfusion in pregnant versus non-pregnant women thus allowing us to calculate a cut-off value using ROC curve for 3D Power Doppler indices. However, incompliance of most of included patients made this kind of follow up unavailable.
• Implications
Although implantation itself is a dynamic process occurring between blastocyst and endometrial layers, the priming of the endometrium towards the window of implantation is of pure maternal origin. A reduced endometrial receptivity is found in an increasing number of unexplained infertilities (62) . Therefore, an inadequate endometrium can be considered as a main fertility-determining factor (94).
Ideally, a technique to assess endometrial function and thereby predict endometrial receptivity must be easily performable within the daily clinical routine and would preferably be non-invasive. These requirements are met by ultrasound measurements (94).
In the present study we used 3D Power Doppler technique for quantitative assessment of blood perfusion of endometrium and sub-endometrium during the mid-luteal phase in women with unexplained infertility or PCOS.
We found that endometrial and sub-endometrial perfusion was decreased in unexplained infertility than in PCOS and both groups had significant decrease in endometrial and sub-endometrial perfusion compared to a control group of fertile women.
We have found no difference between each of the included infertile groups (unexplained and PCOS) and the control fertile group regarding endometrial thickness, endometrial volume, uterine volume and 2D pulsed wave Doppler PI and RI of uterine arteries. Therefore, we suggest that these conventional methods of endometrial assessment are of limited value in assessing women with unexplained infertility or with PCOS.
Although the routine use of 3D Power Doppler as a part of infertility work-up has not been established yet, a previous study has suggested that Power Doppler Energy was a predictive factor of endometrial receptivity (197).
In addition the results of the present clinical study showed that there was no association between endometrial thickness and 3D Power Doppler indices; thus supporting suggestion that the thickness of the endometrium does not reflect its function or receptivity (94).
Most common line of treatment for women with unexplained infertility or PCOS is the use of ovulation induction drugs such as clomiphene citrate (CC) and letrozole.
In PCOS it is suggested that thinner endometrium after CC might affect pregnancy and live birth rates especially that recent studies reported higher pregnancy and live birth rates after letrozole compared to CC (122). However, the present recent systematic review reported very low quality of evidence on that suggestion (125).
Interestingly in women with unexplained infertility a recent meta-analysis found no difference in endometrial thickness after CC or letrozole (169). Furthermore, a recent RCT found that CC resulted in higher pregnancy and live birth rates than letrozole in women with unexplained infertiltiy (198).
Therefore, various treatments, especially during IVF, such as low dose aspirin, heparin, omega-3, angiogenic growth factor and nitroglycerin have been suggested to improve endometrial receptivity due to their promoting effects on uterine perfusion (199-202).
Further larger scaled studies are still needed to assess endometrial and sub-endometrial perfusion in women with unexplained infertility or PCOS using 3D Power Doppler indices with the aim of identifying a cut-off value of these indices to achieve pregnancy thus guiding clinicians to provide an effective patient-tailored treatment plan.
Pre-treatment assessment of women with infertility with 3D-PDA may prove useful as a diagnostic tool or facilitate the development of alternate, less invasive and ultimately more affordable management strategies.
For instance, in unexplained infertility, it might help introduction of adjunctive treatment as aspirin to enhance uterine perfusion during expectant management of unexplained infertility which is recommended for a total of 2 years (this can include up to 1 year before their fertility investigations) before IVF according to NICE guidelines recommendations (5).
Also, in PCOS it might lead to better stratification of patients according to degree of uterine perfusion in heterogeneous variants of PCOS thus facilitating choice of cheaper alternatives to letrozole such as CC, especially in low resourced settings.