Science has strived to reveal each of the details of how Nature works. One of their reasons is to “correct” it when necessary. In the field of human fertility, specifically female fertility, the lengthen the time the window remains open to be a mother.
The ticking of the biological clock is greater in ovaries than in other organs. “The chances of natural pregnancy in a given month are plummet from 25% at age 25 to less than 5% at age 40“says the professor of Obstetrics, Gynecology and Reproductive Sciences at the University of California in San Francisco (USFC), Diana Laird.
The blame for this marked decline is not only the quantity and quality of the eggs, but also the location where they stay: the ovary. “We have shown that the environment surrounding gametes (the supporting cells, nerves and connective tissue) also changes with age,” says Laird.
This statement underscores new insights into female fertility that come from research by a team at USFC and the Chan Zuckerberg Biohub San Francisco. The USFC professor is the main author of the publication of the work in Science.
“Our study shows that the decline of fertility between 30 and 40 years It is not only defined by the decrease in the number of eggs and their capacity for fertilization, but also by changes in the ovarian environment.” In addition, he adds that, as part of the home of the gametes, “we discover the role of the sympathetic nerves and its possible interactions with glial cells and blood vessels in regulating egg growth.”
Gabriele Zaffagniniresearcher at the FMNS-Institute of Genetics (UoC) of the University of Cologne, maintains that this work sheds “a little light on a process that still remains largely obscure.” At the same time, he states that “we can fully understand ovarian aging only if we consider the changes that occur with age in the ovary as a whole.”
Understanding these processes opens the way to development of new methods to correct fertility At the same time, it is possible to act on the impact of early menopause or the consequences of removing an ovary.
Through this study, we try to explain the reason for ovarian aging. Juan Antonio García VelascoGlobal Chief Scientific Officer del IVIpoints out that “one of the possible explanations is the role of the nervous system, which regulates its function.” This organization adjusts ovulation, hormone production, and communication with the brain through neurotransmitters. “Receives and sends instructions to this body. It is key in the cycle,” clarifies García Velasco.
This expert also details the impact of the “home” structure of the ovary. “Outside of it there is a vascular system, connective tissue and the nervous system that regulates all this.. That is where the article focuses.” Therefore, García Velasco explains that “if these tissues are destructured, for example, due to surgery, fibrosis, or some pathology such as cysts or endometriosis, there may be a loss in the number of follicles.”
Alex García-FauraScientific Director of Marquis Institutealso values the considerations that Laird’s work has reached. List the protagonists of that home -“Stroma, blood vessels and glial cells create an essential microenvironment for oocyte maturation“- and argues what happens with age: “this tissue loses elasticity, becomes fibrous and reduces vascularization, making communication between oocytes and somatic cells difficult.”
How were the findings made?
The team of researchers has created a sort of ‘cell atlas’ of the ovary, a map that shows the different types of cells and how they change over time. “By combining the technology of cutting-edge image of the Laird laboratory with the Biohub experience “In two types of single-cell sequencing, we were able to understand the ovary in unprecedented detail,” says Norma Neff, director of the Genomics Platform at the San Francisco Biohub, who collaborated with Laird on the work. “This technological approach allowed us to discover new types of cells, laying the foundation for future discoveries in reproductive health.”
Zaffagnini highlights this progress because “the ovary is a very complex tissue and constantly subject to very important changes due to ovulation cycles. In the ovary the eggs are not isolated, quite the opposite.
The main author of the research explains that they used human models alive and rodents. They both studied to create an aging roadmap through 3D imaging and sequencing of active genes in single cells. Changes in the ovaries of 9- to 12-month-old mice resembled those in 30- to 40-year-old humans in many ways.
“We were lucky to obtain human ovariesbut we did not experiment with them -he specifies-, so this similarity lays the foundation for the use of laboratory mice and the incredible tools available to model human ovarian aging. Studies in mice could accelerate progress toward development of much-needed therapies for infertility and delayed menopause“.
What are the implications for addressing women’s health issues and their impact?
Among the findings already mentioned, Laird dwells on the significance of the discovery of the sympathetic nerves, known for their role in the “fight or flight” response, which also play a key role in regulating the growth of eggs in the ovary. “By genetically inhibiting survival of sympathetic nerves “In mice, we observed more eggs at rest and fewer in growth, which suggests that the nerves participate in the awakening of the eggs in their follicles and in supporting their growth and maturation,” explains the researcher.
“In both humans and mice, we observed that sympathetic nerve networks become denser as reproductive age advances.” Recognize that even unknown how sympathetic nerves and glial cells mediate follicular maturationbut “we found evidence that growth factors are produced by cells that wrap the blood vessels growing around the follicles. All of this points to a triple interaction between nerves, blood vessels and growing follicles that we are currently trying to understand.”
Another point that Laird highlights for its clinical implications to prolong fertility or delay menopause is “the set of nerves and glial cells of the ovary as possible targets for fertility preservation.” The researcher explains how: “By modulating sympathetic signaling, or possibly blood vessel guidance signals, it could be possible to slow down the loss of eggs, thus prolonging the reproductive window and potentially delaying menopause.”
The signaling has three key structures: the sympathetic, parasympathetic and sensory system. “These three systems are fundamental for the production of hormones, folliculogenesis and the hormonal response,” explains García Velasco. Besides, “there is an intrinsic nervous system in the ovary that works together with extrinsic innervation, which is related to these three mentioned systems”.
Here García-Faura points out that “excess sympathetic signaling could contribute to oxidative stress, inflammation and fibrosis of ovarian tissue. “Therefore, the nervous system not only regulates hormonal function, but also directly influences ovarian health and aging.”
An interesting thing, which the IVI spokesperson points out, is that this intrinsic nervous system of the ovary, “we know that sometimes it is altered by a pathology. For example, with polycystic ovary syndromewe know that there is an alteration of the intrinsic nervous system and that causes the ovary to function poorly and ovulate late and there is difficulty in having children.
All of these details would have a big impact since women spend more than a third of their lives postmenopause, Laird insists. Since the onset of menopause is accompanied by an increased risk of cardiovascular disease, “understanding age-related vascular changes in the ovaries may provide clues to improving overall cardiovascular health. We have high hopes that the ovary can provide information to protect cardiovascular health“says the researcher.