Age-associated changes in cumulus cells and follicular fluid: the local oocyte microenvironment as a determinant of gamete quality

Abstract

The ovary is the first organ to age in humans with functional decline evident already in women in their early 30s. Reproductive aging is characterized by a decrease in oocyte quantity and quality, which is associated with an increase in infertility, spontaneous abortions, and birth defects. Reproductive aging also has implications for overall health due to decreased endocrinological output. Understanding the mechanisms underlying reproductive aging has significant societal implications as women globally are delaying childbearing and medical interventions have greatly increased the interval between menopause and total lifespan. Age-related changes inherent to the female gamete are well-characterized and include defects in chromosome and mitochondria structure, function, and regulation. More recently, it has been appreciated that the extra-follicular ovarian environment may have important direct or indirect impacts on the developing gamete, and age-dependent changes include increased fibrosis, inflammation, stiffness, and oxidative damage. The cumulus cells and follicular fluid that directly surround the oocyte during its final growth phase within the antral follicle represent additional critical local microenvironments. Here we systematically review the literature and evaluate the studies that investigated the age-related changes in cumulus cells and follicular fluid. Our findings demonstrate unique genetic, epigenetic, transcriptomic, and proteomic changes with associated metabolomic alterations, redox status imbalance, and increased apoptosis in the local oocyte microenvironment. We propose a model of how these changes interact, which may explain the rapid decline in gamete quality with age. We also review the limitations of published studies and highlight future research frontiers.

Keywords: angiogenesis; apoptosis; epigenome; extracellular matrix; metabolism; mitochondrial DNA; proteome; reactive oxygen species; telomere; transcriptome.

Figure 1

The local oocyte microenvironment. (A) Mouse antral follicle. Asterisk shows antral cavity filled with follicular fluid. Arrow points to the expanding cumulus cells 11 h after human chorionic gonadotropin injection, and arrowheads show mural granulosa cells. (B) The appearance of human antral follicles on ultrasound at the time of oocyte retrieval. Asterisks show fluid filled antral cavity of 18–20 mm follicles.

Figure 2

A schematic diagram of the age-related changes and their potential interactions in the local oocyte microenvironment. ROS, Reactive oxygen species; mtDNA, mitochondrial DNA; cf-mtDNA, cell-free mitochondrial DNA; ECM, extracellular matrix; AGE, Advanced glycation end products; sRAGE, soluble AGE receptor.