Controlled Ovarian stimulation protocols, serum luteal progesterone and immunomodulators in women undergoing assisted conception

Senra Estrela Melo, Pedro (2023). Controlled Ovarian stimulation protocols, serum luteal progesterone and immunomodulators in women undergoing assisted conception. University of Birmingham. Ph.D.

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Infertility affects an estimated 48.5 million couples globally. Approximately 5-10% of couples with infertility require assisted reproductive technology (ART) to conceive a pregnancy. Since the birth of Louise Brown in 1978, ART procedures have evolved to include complex ovarian stimulation protocols, in vitro treatment with cryopreservation of gametes or embryos, and adjuvant interventions aimed at improving reproductive outcomes. However, despite these advances and the growing number of ART cycles performed worldwide, the rates of live birth resulting from assisted conception remain relatively low.
The success of ART depends on a complex biochemical dialogue between the implanting embryo and the endometrium. Factors such as ploidy status and metabolic competency affect embryo quality, while endometrial receptivity involves developing a tolerant immuno-endocrine milieu to the attaching embryo.
This thesis investigates optimisation strategies to improve ART success. I use a range of methodologies, including systematic reviews of randomised controlled trials, network meta-analysis and prospective observational data, to propose tangible ways to enhance treatment effectiveness and improve safety at various stages of assisted conception.
The main findings are:
1. Controlled ovarian stimulation (COS) protocols vary in their effectiveness and safety. The Cochrane network meta-analysis in this thesis confidently demonstrates that short gonadotrophin-releasing hormone (GnRH) antagonist protocols reduce ovarian hyperstimulation syndrome rates in women with predicted normal and high response compared to long GnRH agonist protocols. Notably, the data did not confidently identify a difference in live birth rates between these two main COS protocols.
2. Women with low serum progesterone (<10 ng/ml) undergoing frozen embryo transfer (FET) cycles experience fewer live births and an increased risk of miscarriage compared to women whose serum progesterone level is ≥10 ng/ml.
3. The route of progesterone administration in FET cycles affects the relationship between serum progesterone and the probability of live birth. Women having natural cycle FET (endogenous progesterone) or vaginal progesterone supplementation exhibit a near-linear association between serum progesterone and the adjusted mean probability of live birth, whereas this relationship is non-linear for those receiving exclusively subcutaneous progesterone supplementation for luteal phase support. Combined therapy with vaginal and subcutaneous progesterone may synergistically ensure stable live birth rates irrespective of serum progesterone levels.
4. The evidence for immunological therapies during the luteal phase to improve the rate of live birth in ART is mostly of low or very low certainty, although some drugs may lead to improved outcomes in selected women.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Metabolism and Systems Research
Funders: Other
Other Funders: Tommy's Charity
Subjects: R Medicine > RG Gynecology and obstetrics


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