Abstract
It is well established that female fertility begins to decline in the late 30s, well before the cessation of the reproductive cycle. As societal trends change and individuals choose to have children later in life, there is a growing need to understand the cause of age-related infertility. Women are born with a finite number of oocytes known as the primordial reserve, which is depleted throughout life. A long-standing assumption in ovarian biology suggests that the size of the primordial reserve predicts the age at menopause and has significant implications for fecundity. However, as only cross -sectional data is available on the primordial reserve, these claims have not been verified experimentally.
This work aimed to quantify the primordial reserve in live mice. The ovaries of Figla - Cre Tg/0 –tdTomatofl/0, which express a fluorescent protein in the oocytes, were imaged during a survival surgery. Through the development of a machine learning -powered image analysis pipeline,the images were used to estimate the primordial reserve at 25 days. This was paired with the histological quantification of follicles at the end of life to generate the first longitudinal data on the primordial reserve. This revealed that the rate of primordial follicle loss and not the initial follicle number was a key determinant of late -life primordial reserve. Integrating the patterns of primordial reserve decline into human models of follicle loss show s that the rate of follicle loss is an overlooked variable that may play a key role in determining the age at menopause. Additionally, a cohort of mice with longitudinal primordial reserve measurements was entered into a fertility trial, and no relationship was found between primordial follicle counts and reproductive output.
In fertility medicine, the use of donor oocytes in older women can rescue fertility, suggesting that the uterus is still able to facilitate implantation and maintain a pregnancy. Therefore, attention was turned to the quality rather than the quantity of oocytes in the ovary . It is known that oocyte developmental competence declines with age, but the mechanisms remain poorly understood. By sequencing the RNA transcriptome of naturally ovulated oocytes from 3 -month and 10 -month -old mice, it was identified that proteasomal genes, ubiquitin pathways and meiotic spindle proteins were dysregulated with age. Mitochondrial translation was identified as a novel process that could regulate cellular response to oxidative stress in oocytes. Further functional analysis is needed to confirm the function of genes identified in this study and will inform the development of non-invasive techniques for diagnosing oocyte quality.
Taken together, this work supports an understanding of the end stages of ovarian aging as a regulated biological process where the quantity and quality of oocytes play distinct roles in determining the duration of female fecundity and the reproductive lifespan.