The uterus and ovaries do not age at the same time or in the same way: a Catalan study takes a new X-ray of menopause

Despite affecting half of the world's population and being experienced by all women, little is known about menopause. This is explained by the fact that, historically, it has been underestimated and understudied both from scientific research and also from a clinical perspective. And yet, despite being a natural stage in women's lives that usually occurs around the age of 50, it has an important impact on the health of their tissues and organs, and is associated with an increased risk of developing diseases such as cardiovascular, neurodegenerative, metabolic, and bone diseases.

“It is surprising [this lack of scientific studies]”, points out Marta Melé, head of the Functional Genomics and Transcriptomics research group at the Barcelona Supercomputing Center - National Supercomputing Centre (BSC-CNS). “Our objective is to fill this gap”, assures this researcher, who has just published in Nature Agingthe most important work ever done on female aging in this stage of life.

Melé and her team have discovered that not all organs that form the female reproductive system age at the same time, but rather it is a complex, phased process, during which, for example, the ovaries begin a slow decline about 10 years before the menopausal phase, which would explain the reduction in fertility by the age of 40; while the uterus suffers a very abrupt decline in postmenopause.

“Furthermore, we have identified the genes that drive all the changes we see in the organs, which opens the door in the future to designing prevention strategies”, adds Melé, who emphasizes that, in the end, the objective is twofold: on the one hand, to try to prevent the negative consequences for the overall health of women derived from menopause in order to improve their quality of life. And, on the other hand, to advance towards a more complete understanding of female aging to lay the groundwork for more precise and equitable medicine.

A reorganization of tissues

The BSC team has analyzed, with the help of a deep learning AI and the MareNostrum 5 supercomputer, more than 1,000 tissue images from 304 women aged between 20 and 70 years. Afterwards, they compared the results with data on gene activity in seven organs – uterus, ovary, vagina, cervix, breast, and fallopian tubes – to identify observable changes in both tissues and molecular processes associated with aging in each organ.

“Until now, we tended to consider menopause primarily as the end of ovarian reproductive function. However, our results show that it acts as a turning point that profoundly reorganizes other organs and tissues of the reproductive system, and allows us to identify the genes and molecular processes that could be behind these changes,” explains Melé.

For example, they have found genes associated with reproductive system diseases, such as the nearly 200 linked to pelvic prolapse, a condition that affects 40% of postmenopausal women, which weakens the tissues that support the uterus until it falls, pressing on the vagina. In many cases, it requires surgical intervention. Or genes linked to the rapid decline of vaginal tissue, which would explain the usual vaginal dryness from age 60 onwards.

What is most interesting is that the researchers have found that all these changes in the expression of genes that regulate the aging of the female reproductive system can also be detected in blood. To do this, they have analyzed plasma samples from 21,000 women, looking for proteins linked to each organ to find biomarkers that allow monitoring this process in a minimally invasive way.

“These biomarkers could allow for non-invasive monitoring of the state of the reproductive organs, and anticipate risks associated with menopause, such as pelvic prolapse, without the need for biopsies,” the researchers point out.

With a gender perspective

This new study adds to a previous one by the same BSC group published recently that revealed for the first time that women's immune systems change with age much more than men's. The researchers found that, as women age, the number of inflammatory immune cells increases, which would explain why with aging women are more prone to suffer autoimmune diseases or to suffer the worsening of certain inflammatory diseases after menopause.

“Many studies still do not take sex into account in their analyses, or directly only use data from men, in a way that leaves key questions unanswered. Our research is born precisely from this need and combines a scientific perspective with a sex perspective, inclusive data, and great computational power”, assures Melé.