Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications

Abstract

An equilibrium needs to be established by the cellular and acellular components of the ovarian follicle if developmental competence is to be acquired by the oocyte. Both cumulus cells (CCs) and follicular fluid (FF) are critical determinants for oocyte quality. Understanding how CCs and FF influence oocyte quality in the presence of deleterious systemic or pelvic conditions may impact clinical decisions in the course of managing infertility. Given that the functional integrities of FF and CCs are susceptible to concurrent pathological conditions, it is important to understand how pathophysiological factors influence natural fertility and the outcomes of pregnancy arising from the use of assisted reproduction technologies (ARTs). Accordingly, this review discusses the roles of CCs and FF in ensuring oocyte competence and present new insights on pathological conditions that may interfere with oocyte quality by altering the intrafollicular environment.

Keywords: Cumulus cells; Developmental competence; Follicular fluid; Oocyte.

Fig. 1

Schematic diagram showing the role of the blood-follicle barrier and cumulus cells in follicular physiology. a General view of the antral follicle. b During follicular development, granulosa and thecal cells secrete VEGF, which stimulates follicular angiogenesis to form a complex vascular network. The endothelium, sub-endothelial basement membrane, thecal interstitium, follicular basement membrane, and membrane granulosa constitute the blood-follicle barrier, which restricts the transcellular transport of molecules between the blood and follicular fluid based on molecular size. The constitution of follicular fluid is altered under many conditions (e.g., age, oocyte maturation stage, and blood supply/flow), and this can negatively impact oocyte maturation and oocyte quality. c Cumulus cells (CCs) express the soluble and membrane-bound isoforms of KIT ligand (KITL), which acts on oocyte KIT tyrosine kinase receptors (KITr) to enhance oocyte growth. The oocyte secretes growth differentiation factor 9 (GDF-9) and bone morphogenic protein 15 (BMP-15), which regulate CC proliferation, differentiation, glycolysis (Gly), and cholesterol synthesis (CS). Meanwhile, CCs provide pyruvate, lactate, and products of the cholesterol biosynthetic pathway to the oocyte via gap junctions to support the production of ATP in the oocyte. CCs also transfer ions, cyclic nucleotides (cAMP and cGMP), metabolites, amino acids, and RNA transcripts via gap junctions to the oocyte to support meiosis and help maintain the pH balance of the gamete. As the metabolism of the oocyte and CCs come to resemble one another, any alteration in the somatic cells may affect the competence of the gamete. CCs also defend the oocyte against metabolites, ROS, toxins, and inflammatory markers present in the follicular fluid. Under adverse conditions (e.g., pathologies, infections, or inflammatory processes), the protective effects of CCs may be affected, leading to downstream compromises in steroidogenesis and oocyte development. Maternal aging may also impair oocyte competence, such by perturbing the antioxidant defenses and energy metabolism of CCs and inducing apoptosis in these cells, thereby compromising the oocyte meiotic spindle. Abbreviations: AGE (advanced glycation end-products), AMH (anti-Müllerian hormone), ATP (adenosine triphosphate), Ax (antioxidants), BMP-15 (bone morphogenetic protein-15), cAMP (cyclic adenosine monophosphate), cGMP (cyclic guanosine monophosphate), CAT (catalase), CS (cholesterol synthesis), GDF-9 (growth differentiation factor-9), Gly (glycolysis), KITL (KIT ligand), KITr (KIT receptors), LPS (lipopolysaccharide), miRNA (micro RNA), MMP-2 (metalloproteinase-2), ROS (reactive oxygen species), SOD (superoxide dismutase)