Biomarkers

Infertility and the importance of the endometrial immune balance

BY

Daneel Johnston

Infertility is defined by the World Health Organisation as the inability of a sexually active non-contracepting couple, to conceive after 12 months of regular intercourse, or to remain pregnant following conception. Infertility affects a significant number of couples (10-15%), with approximately 50-80 million people worldwide affected. Fertility issues can be of female (~50% of cases) or male (20-30% of cases) origin, or from a combination of factors that prevent successful pregnancy (https://www.who.int/news-room/fact-sheets/detail/infertility). Infertility can have negative psychological effects on couples, leading to feelings of defeat, inadequacy, depression and shame.

Difficulty in conceiving is far more common than we might expect, but not all couples experiencing fertility issues are infertile. Before turning to in vitro fertilisation (IVF) and other costly alternatives, it is worthwhile investigating whether a couple is in fact unable to reproduce, or whether there is an underlying issue that can be resolved.

Basic infertility tests include medical history and physical examination for both partners, semen functionality assessments, diminished ovarian reserve testing, ovulatory dysfunction testing, and various uterine assessments. While the first recommended fertility test is a sperm count, a couple’s inability to conceive may also be influenced by the immune profile of the endometrium, which can result in recurrent foetal loss in early pregnancy or a complete inhibition of implantation (https://doi.org/10.3389/fimmu.2020.01032).

Recent studies have highlighted the need for certain immune cells to be present in sufficient levels within the endometrium, to allow for embryo implantation and subsequent foetal development to full term (https://dx.doi.org/10.5653%2Fcerm.2011.38.3.119; https://doi.org/10.1016/j.placenta.2020.07.025). A uterine immune reaction window occurs each cycle, in which the human endometrium prepares to accept an embryo for implantation. This is known as the implantation window and occurs 5 to 9 days after ovulation. During this specific period, an immune switch should occur to avoid the rejection of the semi-allogenic embryo, and to promote growth and development of the foetus.

In the implantation window, B cells lymphocytes leave the endometrium, while cells belonging to the innate immune system (macrophages, NK cells, lymphoid cells and dendritic cells) invade the endometrial lining. In addition, regulatory T cells play a dominant role in the maintenance of immunological tolerance by preventing immune and autoimmune responses against self-antigens (https://doi.org/10.1016/0028-2243(91)90058-S). In this context, underactive immune cells may fail to create the necessary implantation environment that allows for successful establishment of the embryo. Conversely, overactive uterine immune cells may lead to a premature endometrial destruction and rejection of the embryo/foetus.

Understanding the local uterine environment may play an important role in anticipating the interaction between the endometrium and the embryo. In a recent study, local endometrial immunity was confirmed to be an important parameter that enabled clinicians to predict the prognosis of pregnancy. Additionally, targeted medical intervention and promotion of adequate immune tolerance within the uterus, resulted in significantly higher pregnancy rates in patients with repeated implantation failures (RIF) and recurrent miscarriages (RM).

The Specialised Diagnostics Unit at Synexa Life Sciences offers endometrial profile testing from menstrual blood, in which the levels of natural killer (NK) cells, B cells and T cells are quantified. In parallel, assessment of the peripheral blood cytokine profile is performed to determine the activity of NK cells and T helper 1 (Th1) and T helper 2 (Th2) cells in circulation.

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