Endometrial receptivity

Craciunas, Laurentiu ORCID: 0000-0001-7952-0647 (2023). Endometrial receptivity. University of Birmingham. Ph.D.

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Abstract

Establishment of successful pregnancy depends upon implantation, involving complex interactions between the endometrium and the blastocyst. It is well accepted that the implantation window is a narrow time frame with maximal endometrial receptivity, surrounded by a refractory endometrial status. Suboptimal endometrial receptivity and altered embryo–endometrial dialogue are responsible for two-thirds of implantation failures manifesting as miscarriage or failed in vitro fertilisation (IVF) treatment following embryo transfer.

The overarching aim of the present thesis was to understand endometrial receptivity and explore the development of potential endometrial receptivity tests that are cost-effective and may be implemented in clinical practice. The thesis is structured into seven chapters with individualised objectives.

Chapter one introduces the topic and summarises the current body of knowledge in relation to endometrial receptivity. Endometrial receptivity is complementary to endometrial selectivity and explains the pathophysiological antithesis between recurrent implantation failure and recurrent miscarriage of endometrial cause.

Chapter two is a Cochrane review of the evidence supporting the use of intrauterine human chorionic gonadotropin (hCG) administration before embryo transfer through its effect on endometrial receptivity. Seventeen randomised controlled trials (RCTs) including 4751 women were meta-analysed to identify an increase in live birth rate (RR 1.57, 95% CI 1.32 to 1.87; three RCTs; 914 participants; I² = 0%; moderate-quality evidence) and clinical pregnancy rate (RR 1.49, 95% CI 1.32 to 1.68; 12 RCTs; 2186 participants; I² = 18%; moderate-quality evidence) for women undergoing cleavage-stage embryo transfer with a hCG dose ≥ 500 IU. There were no substantive differences in live birth (RR 0.92, 95% CI 0.80 to 1.04; two RCTs; 1666 participants; I² = 0%; moderate-quality evidence) and clinical pregnancy (RR 0.99, 95% CI 0.85 to 1.15; four RCTs; 2091 participants; I² = 42%; moderate-quality evidence) among women having blastocyst-stage embryo transfer with a hCG dose ≥ 500 IU.

Chapter three is a comprehensive review of the literature on conventional and modern markers of endometrial receptivity. A total of 163 studies including 88 834 women were reviewed to assess over 40 markers of endometrial receptivity. Associations were identified between clinical pregnancy and various endometrial receptivity markers (endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity and various molecules); however, their poor ability to predict clinical pregnancy prevents them from being used as diagnostic tests of endometrial receptivity.

Chapter four is an assessment of women’s views as part of a target product profile for developing a test of endometrial receptivity. The results from a questionnaire answered by 131 women who suffered recurrent miscarriages support the use of an endometrial receptivity test after two miscarriages and its timing in a window of three to four days within the menstrual cycle with results available within one to two days. The invasiveness of testing should not extend beyond a vaginal examination and repeating the test should not be required more than twice with the results remaining useful for at least six menstrual cycles.

Chapters five and six explore the use of transcriptomics and metabolomics for the base of an endometrial receptivity test. A total of 24 women who suffered unexplained recurrent miscarriages underwent endometrial biopsies during the window of implantation to identify differently expressed genes and metabolites between 1) women who suffered low order miscarriages and those who suffered high order miscarriages; and 2) women who achieved a live birth and those who suffered another miscarriage in the subsequent pregnancy. Women who suffered higher order miscarriages had 19 differently expressed genes and perturbations in the fatty acid metabolism and poorer mitochondrial health. Women who achieved a subsequent live birth had 421 differently expressed genes and perturbed cholesterol - cholesterol sulphate metabolism, fatty acid metabolism, and improved mitochondrial health.

Chapter seven integrates the findings from previous chapters and concludes the thesis. All five original studies have been published in peer reviewed journals.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):