Nova YorkThe egg has become a dominant source of anxiety for many women. Human eggs are finite and decline in both quality and quantity with age. From the age of 30, it becomes more difficult to get pregnant, and at menopause the woman is left without functional eggs. Growing awareness of this reproductive reality has led to an increase in egg freezing as women try to preserve their vitality. But infertility goes beyond aging eggs. Recent research is paying more attention to the ovaries.
There is growing evidence that the age of an ovary, and not just the number of eggs it contains, is important for reproduction and healthy aging. This includes the cells and tissues that make up the environment surrounding a woman’s eggs, such as supporting cells, nerves and connective tissue.
The tissues surrounding the follicles – fluid-filled sacs that contain an immature egg – can change with age, and even become fibrotic. Research has shown that this can harm the quality of eggs, reduce the number that mature each month, and block ovulation. Fibrosis is common in many aging organs, where thick scar-like tissue builds up. But in the ovaries it occurs decades earlier.
As scientists seek treatments for age-related infertility as well as menopause, they need to understand the entire cast of characters in the ovary. “You can’t separate the health of the egg from the health of other cell types,” says Evelyn Telfer, professor of reproductive biology at the University of Edinburgh. In other words, the egg may be the leading actress, but it needs supporting actors.
The ovary is an exceptionally dynamic organ. It is both an egg reservoir and a hormone producer that drives egg-containing follicles through the biological choreography known as folliculogenesis. This is ultimately what results in monthly ovulation. The follicles are surrounded by supporting tissues within a skeleton-like structure called the extracellular matrix. These tissues and the cells they contain, collectively called the stroma, are the focus of recent research.
In 2014, in Francesca Duncan’s lab at the University of Kansas Medical Center, a technician noticed something peculiar while studying the development of early-stage ovarian follicles. In the older mice, the surrounding tissue appeared to harden, making it difficult to extract the follicles. In her training as a reproductive biologist, Duncan had learned to despise most of the components of the ovary: anything other than the egg and its follicle was literally discarded. But what he observed in mice made it clear that other tissues might be critical to egg development.
“The egg needs this whole village,” says Duncan, who is now a professor of reproductive sciences at Northwestern University Feinberg School of Medicine. The follicle itself produces the key hormones that drive egg development, but more recent studies have shown that other tissues in the ovaries can influence the production of these hormones. Recent research has shown that if mouse follicles growing on a plate are suspended in stiffer substances, the follicles produce different hormone profiles and ultimately poorer quality eggs. In other words, the environment of the ovary directly influences the quality of the egg.
Another Northwestern researcher, Monica M. Laronda, has found that aging may be influenced not only by follicular hormones, but also by hormones produced by the stroma. At least some of these stromal hormones appear to increase with age. In other research, Laronda found that placing minced human ovarian stroma in a Petri dish with mouse follicles improved follicle growth. It is another fact that indicates that these tissues are necessary for the health of the eggs and ovaries.
A blood analysis for the ovarian reserve
In a recent comparative study of human and mouse ovaries at different stages of age, Diana Laird of the University of California, San Francisco, discovered that the density of sympathetic nerves surrounding ovarian follicles increases with age. At the same time, the blood vessels surrounding the follicles begin to decrease in density. He said they could be key signs of follicular well-being and overall health. He hopes to design a blood test that can assess the health of a woman’s ovarian reserve.
All of this knowledge points to new ways to not only treat infertility, but also potentially delay the harmful side effects of menopause, such as bone loss and the risk of heart disease. The work of Rebecca Robker, a reproductive biologist at the University of Adelaide, Australia, has shown that ovarian fibrosis can be reversible. In a 2022 study, he showed that a drug used to treat pulmonary fibrosis made old mice ovulate.
Duncan’s lab is now testing anti-fibrotic drugs that could benefit ovarian health. These treatments could one day be given to patients struggling to have children before trying fertilization in vitroor even in women who want to delay menopause.
Drugs that are popular with longevity enthusiasts, such as metformin and rapamycin, are also being studied to see if they can slow ovarian aging. But in many ways, the ovary remains enigmatic. Scientists still do not understand many of the molecular signals and cellular interactions that drive egg development and aging. Since the ovary ages faster than any other organ in the human body, understanding it could be a major advance in our understanding of aging, says Jennifer Garrison, a neuroscientist and assistant professor in UCSF’s department of cellular and molecular pharmacology. “The ovary is complex; it’s important not to underestimate it,” she warns.
