Follicular fluid cytokine measurements: another window into diagnosis and therapy for our patients

Posted By Dr. Braverman || 6-Mar-2015

Follicles are the structural units forming the ovary. They are small vesicles, each containing an immature oocyte that grows and gives rise, monthly to one single fertilizable egg.
Along with hormones and growth factors, follicular fluid (FF) contains cytokines involved in the follicle maturation, some of which have been associated with oocyte quality and its subsequent ability to achieve fertilization (competence).

Until recently an oocyte potential was only determined by morphological parameters which allowed us to detect poor quality oocyte with no real positive predictors of a good quality embryo. New literature is now emerging and shows that FF constitutes a microenvironment directly impacting oocyte quality thus embryo development during human In Vitro Fertilization (IVF).

FF markers: oocyte competence and embryo quality

An improved oocyte quality and fertilization rate have been linked to higher levels of follicular pro-inflammatory cytokines such as IL-1β, IL-6, -15 and -18 as revealed by several studies in infertile women undergoing IVF procedure. These cytokines are involved in the follicle maturation and ovulation. As an example, IL-1β facilitates the rupture of the follicle to release the oocyte and follicular IL-18 levels are positively correlated with the number of oocytes retrieved during a stimulated cycle. High levels of follicular soluble HLA-G predict the failure of fertilization; it also inhibits IL-1β thus preventing a harmonious follicle maturation. Higher levels of follicular granulocyte colony-stimulating factors (G-CSF) and anti-inflammatory cytokine IL-8 have been correlated with follicle growth and good quality oocytes (our data has shown an almost 10-fold increase in G-CSF levels in our patients treated with G-CSF).

Subsequent embryo quality can also be assessed by follicular cytokine screening. While the pro-inflammatory cytokine IL-12 shows contradictory results regarding oocyte quality, data clearly displayed that higher follicular IL-12 levels are found in oocytes generating fragmented embryos. In the same way, high levels of follicular cytokine IL-2 and interferon gamma (IFN-γ) are related to asynchronous embryo development (early cleaving embryos). G-CSF is highly elevated in follicular fluid of oocyte giving embryos with the highest implantation potential.

Most importantly, some follicular factors can even predict the pregnancy outcome. A recent study showed that lower serum levels of IL-8 correlated with a higher risk for extra uterine pregnancy. The chemokine macrophage inflammatory protein-1 beta (MIP-1β) is associated with successful IVF-induced pregnancy when elevated in the follicular fluid.
While follicular granulocyte colony-stimulating factors (G-CSF) is a strong marker of oocyte competence, accumulation of evidence shows that higher follicular G-CSF levels are associated with higher rates of live birth for equivalent good grade embryos.

Follicular cytokines in PCOS and endometriosis

Patients with Polycystic Ovary Syndrome have an excess of insulin and androgen production that severely impact the follicular microenvironment and alter the oocyte development. An impaired oocyte quality in PCOS patients has been linked with elevated follicular fluid levels of tumor necrosis factor alpha (TNF-α) and interleukins IL-13. High levels of follicular leptin are linked to obesity and insulin resistance and have also been correlated with a lower live birth rate.

Women with endometriosis have higher follicular levels for IL-23, IFN-γ and tumor necrosis factor alpha (TNF-α) compared with healthy control individuals. These factors are leading to an inflammation that could negatively impact oocyte quality and be responsible for the poor IVF outcome in women with endometriosis.

By screening follicular fluid composition we here, at Braverman Reproductive Immunology, may be able to detect harmful factors that contribute to poor oocyte quality. Many patients with immune issues have altered cytokine levels in the serum and abdominal cavity. Measurement of FF cytokine levels at the time of egg retrieval will allow us to adapt immune therapy in subsequent IVF stimulations, compare changes in FF cytokine composition and assess the efficacy of treatment(whether that treatment is medical or surgical). Altogether, this will help minimize the rate of failed embryo transfers due to the quality of eggs developed. We are currently developing tailored-strategy therapies to manipulate the follicular fluid components, improve egg quality and increase the chance of a successful pregnancy.

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