Breaking · Post Line
When Francesca Duncan decided to take a look at what was going on in postmenopausal ovaries, she assumed she wouldn’t find much of interest. In a woman’s reproductive years , the ovary is exceptionally dynamic, shifting form and function from day to day throughout her cycle. But after menopause, when egg supply has dwindled and hormone production has waned, the ovaries are often thought of as little more than empty sacks .
“I assumed it was just sitting there inert,” says Duncan, a reproductive biologist at Northwestern University, who was only looking at postmenopausal ovaries as part of a project to map a cellular aging process called senescence throughout the body. Instead, Duncan found that aged ovaries were anything but stagnant. When looking at the protein composition of ovaries of postmenopausal women between the ages of 50 and 75 years old, her team found that the molecular signatures differed significantly across the decades.
The oldest ovary looked nothing like a 60- or 70-year-old organ at the molecular level. She was shocked. “Clearly something is still happening,” says Duncan.
The question is: what? A new wave of discovery is forcing researchers to recast the ovary not as an egg factory with an expiration date, but as an organ that impacts a woman’s overall health and may shape the trajectory of aging long after the fertile years have passed. What they are only beginning to understand is whether changes to the ovary after menopause are harmful, protective, or some combination of the two, shifting over time.
This isn’t the first time the ovary’s role in maintaining health has been underestimated. For decades, surgeons removed healthy organs during hysterectomies, figuring they weren’t doing much besides posing cancer risks. But 20 years ago, evidence began accumulating that removing healthy ovaries actually harms a woman’s overall health, finding an increased risk of dementia , cardiovascular disease , and premature death .
Because the ovary has historically been understood primarily as a reproductive organ, though, research has largely ignored what might be happening once those functions decline. “We don’t even know much about what the premenopausal ovary is doing outside of fertility,” says Jennifer Garrison, an ovarian aging expert and founder of a women’s health biotech company currently in stealth mode. After menopause, the extent of what we know about the ovary basically boils down to “it’s important,” she adds.
Biologists have known for decades, for instance, that after menopause, ovaries continue producing hormones , including testosterone and small amounts of estrogen. But arguments continue over the clinical significance of those hormones. And hormones are only part of a complex signaling system.
Generally, the hormones the ovary produces postmenopause are known to help maintain libido, bone, and muscle, among other things, although it’s not clear how much the relatively small amounts produced by the postmenopausal ovary contribute to those effects. Multiple studies demonstrate that women who undergo oophorectomies fare worse than those who do not, particularly when having their ovaries removed before going through menopause naturally. Recent brain-imaging work by Pauline Maki at the University of Illinois at Chicago shows that even low levels of estrogen circulating postmenopause may matter: Women with higher levels had better-functioning memory circuits when performing memory tasks.
Where that estrogen comes from—and how much the ovary contributes—isn’t as clear. After menopause, evidence suggests the brain reorganizes, possibly to compensate for declining estrogen levels. Maki hypothesizes that ovarian signaling may contribute to that adaptation, and that hormone therapy could alter the relationship between the ovary, the body’s circulating estrogen, and the brain.
The significance of residual hormone production may decrease over time. Still, says Walter Rocca, a professor of epidemiology and neurology at the Mayo Clinic, that doesn’t mean the ovary has become unimportant. “I am convinced until proven otherwise that removing ovaries even after menopause is not advisable,” he says, with a caveat for women at an increased risk of ovarian cancer.
Just how long that importance persists after menopause is still an open question, says Stephanie Faubion, medical director of the Menopause Society. It’s also unclear, she says, how much the answer may vary from woman to woman. “We just have huge gaps,” she says.
Duncan’s work suggests one reason the importance of the postmenopausal ovary may change over time. In analyzing human ovaries, the team found that protein patterns in older ovaries suggested that the ovary becomes a more inflammatory environment. To better understand what may be driving those changes, they looked more closely at the ovaries of mice.
The research, published in June in the journal Molecular Human Reproduction , suggests that the ovary may eventually take on a completely new identity after menopause. The team compared the ovaries of two-month-old mice, reproductively old 18-month-old mice, and post-reproductive 24-month-old mice, and found that over time, the genes linked to inflammation and immune activity became far more active. The number of immune cells in the ovary also increased.
While research on mice does not always translate to humans, it could help to explain the molecular changes Duncan observed in human ovaries. “We think that a lot of those changes may make the ovary more prone to age-related diseases like ovarian cancer,” says Birgit Schilling, an aging researcher at the Buck Institute for Research on Aging who collaborated with Duncan on the human ovary work, which has been published as a preprint . After menopause, the risk of a host of conditions goes up, including stroke, heart disease, and osteoporosis.
Other organs undergo immune remodeling with time, but the ovary ages long before most other organs. Duncan’s work raises the question of whether at some point, the benefits of keeping the ovaries may be outstripped by the risk: As the aging ovary becomes more inflammatory, she wonders whether it may begin broadcasting inflammatory signals to other parts of the body. David Pépin is probing another possibility: that as follicles that house growing eggs disappear, the ovary may also reorganize to preserve hormone production.
Pépin, a reproductive biologist at Massachusetts General Hospital and Harvard Medical School, found that years after cats were given an experimental birth-control gene therapy that prevented their follicles from maturing, the cats were still producing the hormones estrogen, testosterone, and inhibin at completely normal levels. Follicles drive much of the hormone production during a reproductive cycle; without them, hormone levels should have fallen. In preliminary work he has publicly presented but not yet published, Pépin’s team found that when the ovaries were eventually removed, other cells in the ovary—the stroma—appeared to have taken over hormone production.
Pilot studies in mice suggest a similar effect. Pépin thinks he may have tapped into a natural mechanism that helps maintain hormone production as follicles wane. It's long been hypothesized that the stroma may be responsible for some of the human ovary's postmenopausal hormone production.
Estrogen, he says, is not the only hormone that plays a role in menopause. “We know so little about how the other ovarian hormones that are disrupted at menopause may contribute to health,” he says. “It is not a dead organ.”
Source: WIRED
