Endometriosis and assisted reproduction technology

Abstract

Endometriosis is a disease that is historically known to present in many guises. Since 13th century it has been metaphorically regarded as an animalistic womb causing female hysteria. Albeit widely researched, significant controversies that surround the disease remain unsolved, from the clinical presentations, diagnosis, right through to its management strategies. Despite the rapid advancement of technology in modern medicine, the ideal diagnostic and investigative tool of the disease remains elusive, and hence the management of the disease remains a challenge to clinicians. Whilst it is long known that endometriosis is detrimental to fertility, it is unclear if Assisted Reproductive Technology (ART) obliterates that risk.

This thesis aims to investigate the impact of different stages and types of endometriosis on ART outcomes, and how various surgical interventions influence the reproductive outcomes. The thesis will also focus on answering two important questions in endometriosis research, that of whether and how endometriosis impacts on 1) the developing oocytes and embryo, and 2) the endometrium.

The thesis begins with the introduction of two robust systematic reviews and meta-analyses, which concluded that women with endometriosis had a lower pregnancy rate and fewer oocytes retrieved during ART. Worse reproductive outcomes were found in those with more severe disease. Surgical treatment, which traditionally is thought to be beneficial, was found to result similar reproductive outcome in diseased and controls, and possibly more harm. Gathering evidence retrospectively from the IVF databases supported the former conclusion that women with endometriosis undertaking ART had lower number of oocytes collected from matured follicles, and further investigation into the laboratory details showed that women with endometriosis had a higher proportion of early embryo arrest. A mouse oocyte model was then utilised to explore the influence of follicular fluid of women with endometriosis on oocyte development. The study found that follicular fluid retrieved from women with endometriosis results in the activation of DNA damage response pathway, which in turn prevented normal oocyte maturation. These effects were found reversed by the agent resveratrol.

The thesis concludes with a biomarker discovery study on the endometrium of women with endometriosis compared to controls using a highly sensitive and specific state of the art proteomics analysis method (liquid chromatography mass spectrometry with isobaric tag for relative and absolute quantitation (LCMS/MS iTRAQ®) which uncovered unique proteins not yet described in the literature.

Endometriosis is a disease that is detrimental to the reproductive outcomes of those undergoing ART. Its influence on reproduction is complex, but it is now clear that its impact on reproduction does not stop at the traditionally viewed anatomical distortion with resultant subfertility; but have far reaching consequences including that of defective oocyte and embryo development, with a differential impact on the endometrial proteome. The solution to this challenging disease partly lies in the early diagnosis and treatment of the condition; as such not withstanding pitfalls and fallacies surrounding biomarker discovery research, the ultimate validation of a diagnostic panel of biomarkers for the non-invasive diagnosis of endometriosis is now urgently needed.

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Identifiers

ORCID for Ying Cheong: orcid.org/0000-0001-7687-4597

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