Mechanisms of endometrial aging: lessons from natural conceptions and assisted reproductive technology cycles

Abstract

Until recently, the study of age-related decline in fertility has focused primarily on the ovary; depletion of the finite pool of oocytes and increases in meiotic errors leading to oocyte aneuploidy are well-established mechanisms by which fertility declines with advancing age. Comparatively little is known about the impact of age on endometrial function. The endometrium is a complex tissue comprised of many cell types, including epithelial, stromal, vascular, immune and stem cells. The capacity of this tissue for rapid, cyclic regeneration is unique to this tissue, undergoing repeated cycles of growth and shedding (in the absence of an embryo) in response to ovarian hormones. Furthermore, the endometrium has been shown to be capable of supporting pregnancies beyond the established boundaries of the reproductive lifespan. Despite its longevity, molecular studies have established age-related changes in individual cell populations within the endometrium. Human clinical studies have attempted to isolate the effect of aging on the endometrium by analyzing pregnancies conceived with euploid, high quality embryos. In this review, we explore the existing literature on endometrial aging and its impact on pregnancy outcomes. We begin with an overview of the principles of endometrial physiology and function. We then explore the mechanisms behind endometrial aging in its individual cellular compartments. Finally, we highlight lessons about endometrial aging gleaned from rodent and human clinical studies and propose opportunities for future study to better understand the contribution of the endometrium to age-related decline in fertility.

Keywords: aging; assisted reproductive technology; endometrial microbiome; endometrial receptivity; endometrium; pregnancy; senescence.

FIGURE 1

Ovarian and endometrial events in the human menstrual cycle. In the proliferative phase, estradiol secreted from the developing follicle leads to growth and development of the endometrium (left). Magnified inset shows that multiple cell types comprise the endometrium: epithelial, stromal, stem, immune and endothelial. Following ovulation, in the secretory phase, the endometrium undergoes various transformative events, including stromal cell decidualization, in preparation for possible embryo implantation (right). Images created with Biorender.com.

FIGURE 2

Mouse and Human Comparative Reproductive Anatomy and Physiology. Female mouse uteri contain two horns, while human uteri generally have a single cavity. The mouse estrous cycle is composed of proestrus, estrus, metestrus and diestrus stages, with ovulation marking the transition from proestrus to estrus. The human menstrual cycle is divided into the proliferative and secretory phases, with ovulation marking the transition between the two. In the mouse, the trigger for stromal cell decidualization is embryo implantation, after which stromal cells undergo mesenchymal to epithelial transition and adopt the decidualized phenotype. In the human, the trigger for decidualization is ovulation. Images created with Biorender.com. ^†Reprinted from “Vascular changes in the cycling and early pregnant uterus” by Massri N, Loia R, Sones JL, Arora R, Douglas NC, 2023, JCI Insight. 2023 June 8; 8 (11):e163422. Copyright [2023] by the American Society for Clinical Investigation. Reprinted with permission.

FIGURE 3

Cellular Compartments of the Endometrium Undergo Age-Related Changes Which May Contribute to Adverse Pregnancy Outcomes. (A) The endometrium is composed of two layers—the functionalis (upper two-thirds), and the basalis (lower one-third)—and contains various cellular compartments including epithelial, stromal, vascular and immune. (B) The cellular compartments of the endometrium undergo age-related changes including impaired decidualization, increased fibrosis, vascular calcification, alterations in the microbiome and immune cell populations, increased oxidative stress, and cellular senescence. (C) These changes may contribute to the early and late pregnancy complications observed with age. Images created with Biorender.com.