Endometrial receptivity in women of advanced age: an underrated factor in infertility

Abstract

Background: Modern lifestyle has led to an increase in the age at conception. Advanced age is one of the critical risk factors for female-related infertility. It is well known that maternal age positively correlates with the deterioration of oocyte quality and chromosomal abnormalities in oocytes and embryos. The effect of age on endometrial function may be an equally important factor influencing implantation rate, pregnancy rate, and overall female fertility. However, there are only a few published studies on this topic, suggesting that this area has been under-explored. Improving our knowledge of endometrial aging from the biological (cellular, molecular, histological) and clinical perspectives would broaden our understanding of the risks of age-related female infertility.

Objective and rationale: The objective of this narrative review is to critically evaluate the existing literature on endometrial aging with a focus on synthesizing the evidence for the impact of endometrial aging on conception and pregnancy success. This would provide insights into existing gaps in the clinical application of research findings and promote the development of treatment options in this field.

Search methods: The review was prepared using PubMed (Medline) until February 2023 with the keywords such as 'endometrial aging', 'receptivity', 'decidualization', 'hormone', 'senescence', 'cellular', 'molecular', 'methylation', 'biological age', 'epigenetic', 'oocyte recipient', 'oocyte donation', 'embryo transfer', and 'pregnancy rate'. Articles in a language other than English were excluded.

Outcomes: In the aging endometrium, alterations occur at the molecular, cellular, and histological levels suggesting that aging has a negative effect on endometrial biology and may impair endometrial receptivity. Additionally, advanced age influences cellular senescence, which plays an important role during the initial phase of implantation and is a major obstacle in the development of suitable senolytic agents for endometrial aging. Aging is also accountable for chronic conditions associated with inflammaging, which eventually can lead to increased pro-inflammation and tissue fibrosis. Furthermore, advanced age influences epigenetic regulation in the endometrium, thus altering the relation between its epigenetic and chronological age. The studies in oocyte donation cycles to determine the effect of age on endometrial receptivity with respect to the rates of implantation, clinical pregnancy, miscarriage, and live birth have revealed contradictory inferences indicating the need for future research on the mechanisms and corresponding causal effects of women's age on endometrial receptivity.

Wider implications: Increasing age can be accountable for female infertility and IVF failures. Based on the complied observations and synthesized conclusions in this review, advanced age has been shown to have a negative impact on endometrial functioning. This information can provide recommendations for future research focusing on molecular mechanisms of age-related cellular senescence, cellular composition, and transcriptomic changes in relation to endometrial aging. Additionally, further prospective research is needed to explore newly emerging therapeutic options, such as the senolytic agents that can target endometrial aging without affecting decidualization. Moreover, clinical trial protocols, focusing on oocyte donation cycles, would be beneficial in understanding the direct clinical implications of endometrial aging on pregnancy outcomes.

Keywords: cellular senescence; decidualization; endometrial aging; endometrial receptivity; epigenetics; oocyte donation.

Advanced age may negatively affect the endometrial functioning, therefore further research is needed to understand the exact mechanisms involved and impact on receptivity and pregnancy outcomes Created with BioRender.com (https://biorender.com/).

Figure 1.

Method flow chart illustrating the identification and screening of literature for this narrative review of aging and the endometrium.

Figure 2.

Cellular senescence in normal and aged cells. The phenomenon of cellular senescence occurs in different types of human tissues, including endometrium. It involves the transformation of both proliferative and post-mitotic cells into senescent cells in response to various types of stressors. These stimuli can be telomere shortening, epigenetic changes, DNA damage, oxidative stress, chronic mitogen signalling, and mitochondrial dysfunction over a period, which leads to cell proliferation arrest. Additionally, exogenous sources, such as ionizing radiation, ultraviolet light, and environmental toxins, can contribute as stressors resulting in cellular senescence. In normal conditions, the fully senescent cells are targeted by immune cells to be eliminated from the immune system, whereas during circumstances of aging the immune system is unable to clear senescent cells, which leads to the accumulation of senescence-associated secretory phenotype (SASP) and a persistent pro-inflammatory environment. Created with BioRender.com (https://biorender.com/).

Figure 3.

Relation between decidualization and cellular senescence in normal conditions and during the aging process. (a) Normal physiological conditions: in the mid-secretory phase, under the influence of P4 and cAMP, the endometrial stromal cells escape from the cell cycle at the G0/G1 phase and undergo cell differentiation pathways to transform into decidual cells, in the process called decidualization. In the initial phase during decidualization, the subpopulation of senescent cells is present along with the mature decidual cells. Senescence-associated secretory phenotype (SASP) manifested by the endometrial cells is essential for developing an adequate pro-inflammatory response required for the secretion of cytokines, chemokines, and cell adhesion ligands that are pre-requisites for embryo implantation. In the later phase, mature senescent cells are targeted by the immune cells, decreasing the levels of SASP and shifting the endometrial milieu to the anti-inflammatory response that is required to maintain a semi-allogeneic embryo during the pregnancy. (b) During the aging process: in a chronic condition like aging, the immune cells cannot eliminate the mature senescent cells during decidualization. This results in the accumulation of pre-senescent, fully senescent cells and secreted SASP causing persistent unregulated pro-inflammation during mid-secretory endometrium. This fails to maintain the inflammatory balance leading to impaired decidualization and defective endometrial receptivity. Created with BioRender.com (https://biorender.com/).

Figure 4.

Oocyte donation: a model to study recipient aging and her endometrial receptivity. The reported studies have been divided into three arms: oocytes donated by healthy oocyte donors which were transferred to younger recipients or those of advanced age (left); a single pool of oocytes donated by a young woman and distributed among young and advanced age recipients (middle); and infertile patients undergoing IVF who had shared their oocytes with other recipients of advanced age: standard IVF with own oocytes versus IVF with donated oocytes (right). AA, advance age. Created with BioRender.com (https://biorender.com/).