The other day I saw a patient who is in her late 40s. She was feeling great but, like many women today, has been reading and thinking and hearing a lot about menopause and aging. She asked me about hormone therapy and then transitioned to questions about delaying menopause. She had detailed questions about medications and surgeries that might prolong the reproductive years.
My patient’s curiosity was not related to a desire to have more children. Rather, she was curious about a new kind of “fountain of youth,” because she had heard that people who go through menopause later live longer. Is there any truth to this?
How are ovarian aging and longevity linked?
Researchers have observed that, on average, women who have menopause particularly late (after age 55) and women who have their last pregnancy late (after age 33) live longer than women who have primary ovarian insufficiency, or POI (menopause before age 40), and early menopause (before age 45). This doesn’t mean that having a baby in your early 40s causes you to live longer. Instead, it is more likely that a later menopause is an indicator of slower aging overall. And the fact that some women are able to become pregnant in their 40s means that their ovaries (and thus their body as a whole) are aging more slowly than is typical.
Conversely, women who experience POI and early menopause are at increased risk for cardiovascular disease, which is the leading cause of death among women in the U.S. For many years, we thought that much of the benefit of later menopause was exposure to estrogen for longer and later decreased the risk of cardiovascular disease. Proving this idea was the main goal of the Women’s Health Initiative. However, further research into treating women with estrogen in hopes of preventing chronic health problems has failed to yield definitive results.
Instead, perhaps there is something more about having menstrual cycles, beyond estrogen, that helps women maintain good metabolic health. If that is true, then maybe the goal shouldn’t be replacing estrogen but prolonging the ovarian function. Some researchers are studying how to do just that.
How can we prolong ovarian function?
The authors of a 2023 review article discuss a number of possible techniques for slowing ovarian aging and prolonging ovarian function. The interventions they discuss include surgical techniques, lifestyle changes, and medications. An ideal intervention would be started while a woman’s ovaries were still functioning, would be safe during pregnancy and breastfeeding, and safe over a prolonged period of time. The goal as they define it would be to intervene during a woman’s peak reproductive years, perhaps a decade or more before her last menstrual period is expected.
Lifestyle changes
Cigarette smoking is associated with early menopause, and smoking cessation reduces the risk of myriad chronic diseases. While cigarette smoking rates have fallen, about 10% of women in the U.S. still smoke. This intervention is a no-brainer. There are virtually no downsides to quitting smoking if you are among the 10% who do it.
Low-calorie diets also show promise. A number of mouse studies have shown that reducing calorie intake by about 30% prolongs lifespan. And in mice that are genetically modified to experience menopause (most animals, including mice, do not naturally experience menopause), cutting calories by 30% prolongs ovarian function. However, there are no similar studies in humans, and maintaining such a low calorie intake would be difficult for most of us to sustain for a prolonged period of time.
Surgical interventions
Some studies have looked at resecting and preserving a piece of the ovary to reimplant later. Initially, these studies were done to preserve the fertility of young women undergoing chemotherapy or radiation to treat cancer. While there has been some success getting the piece of ovary to function after it is reimplanted in the woman’s body, there are several issues that make this option less than ideal. First, ovarian resection is associated with an increased risk for POI and early menopause. This is the opposite of the goal to prolong ovarian function. The reimplanted piece of ovary functions only, on average, for just over two years. Plus, all these procedures are invasive. Invasive procedures are typically riskier than non-surgical options. Ovarian resection and reimplantation is not likely to be the best option for prolonging ovarian function in most women.
Medications
Medications seem like the most viable option for prolonging ovarian function. There is interest in a number of existing medications, some of which I have written about before and some of which are new.
Three medications that have shown promise in animal studies were originally developed to treat Type 2 diabetes: metformin, acarbose, and SGLT2 inhibitors (marketed under the brand names Jardiance, Farxiga, Invokana, and Steglatro). Researchers have been interested in metformin in particular for its possible effects on how cells age, not just in the ovary but throughout the body. They theorize that reducing the levels of sugar in the blood leads to less inflammation. Inflammation seems to cause stress and damage at the cellular level that ultimately causes tissues to age.
Another medication, rapamycin, has been shown to prolong ovarian function in mice and to improve markers of ovarian reserve in women, though studies so far are small. It works entirely differently from the diabetic medications, and its actions seem to be more specific to the ovary.
Each month, dozens of immature eggs start to mature, but along the way, all but one or two of those eggs drop out of the race. This process is responsible for a large part of ovarian aging. Rapamycin limits the number of eggs that start down the maturation path, from about 50 to about 15. In theory, this means that rapamycin could slow ovarian aging significantly.
Who might benefit from slowing ovarian aging?
The most obvious use for treatments that slow ovarian aging would be to prevent POI and early menopause in women at risk — women with certain genetic mutations, a family history of POI or early menopause, a history of ovarian surgery, or a diagnosis of diminished ovarian reserve. Women who are at risk of experiencing their last menstrual period at an early age could benefit from both preserving fertility for those women who wish to and preventing the health risks associated with POI and early menopause. Current options for preserving fertility, including egg and embryo freezing, are not always successful for these women. And hormone therapy has not been shown to definitively reduce the risk of cardiovascular disease in women with POI and early menopause.
Beyond POI and early menopause, will treatments that prolong ovarian function be the fountain of youth my patient sought? That is less clear. There are no large-scale trials of the medications above developed specifically to look at how they affect ovarian aging and aging in general in a diverse group of women.
It may be a while before studies like that are published. Large clinical trials are expensive. Without a pharmaceutical company paying for the trial, getting funding for clinical trials of generic medications can be difficult. The Targeting Aging with Metformin trial was announced a few years ago, but researchers are still trying to raise money to fund it. As a result, we don’t know how slowing ovarian aging might affect the long-term health of typical women, and we may not have the answer for a long time.
The bottom line
- Having your last pregnancy or your last period when you are older is associated with living longer. This has led researchers to hypothesize that prolonging ovarian function may allow women to live longer, healthier lives.
- There is data, mostly from animal studies, that suggests that interventions such as reducing caloric intake and giving medications including metformin and rapamycin can prolong ovarian function. These studies could lead to important treatment options for women at risk for primary ovarian insufficiency and early menopause.
- There is no data to suggest that all women would benefit from prolonging ovarian function.
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I am very curious how a hysterectomy impacts ovarian aging as it seems many women undergo this procedure. Is anyone able to comment on this?