Is it Perimenopause or Is It Aging?

Be very carful about drawing sweeping conclusions

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Have you noticed a sudden change in health in your mid-40s?

If you spend any time on social media, you would not be faulted for thinking that almost every symptom you are experiencing is the menopause transition (a.k.a. perimenopause).

One of the issues in understanding what is caused by menopause and what it is not, is that aging and menopause happen simultaneously. This is why longitudinal studies that follow women over time, such as SWAN (Study of Women’s Health Across the Nation) or the Penn Ovarian Aging Study, are so critical.

One assumption that many people make is that aging is a linear experience. I admit, I always thought of it in that way, believing I might be the same percentage weaker or have the same percentage less energy each year. Or for example, my cells might age overall by 1-2% a year, according to a variety of biomarkers, every year in a straight line. Interestingly, it was my dad, who several years ago first made me think of aging as a nonlinear process. He told me that in his experience the change from 80 to 85 was far more impactful and profound than the change from 75 to 80, and that he felt far older at 85 than he did at 80 (he was riding his bike all around Winnipeg in the summer even when he was 80!). Looking back over 85 years gives you an interesting perspective. But, of course, that is an n of one and my dad wasn’t tracking his activities and health day to day over the previous twenty or thirty years.

However, there have been a few recent papers that challenge the notion that aging is linear, and I think the concept is worth discussing, because it should shape how we think about the menopause transition as well as the design of studies that look to study the menopause transition (perimenopause).

The most recent study (Shen et. al.) involved 108 participants. The researchers evaluated a lot of markers associated with aging, for example, testing that tells us about immune regulation, inflammation, the microbiome (internal and external), carbohydrate metabolism, cardiovascular disease, lipids, and alcohol metabolism. The study participants were aged 25 to 75 and were tested every 3-6 months, including blood, stool, skin, oral, and nasal swabs. The average length of testing was just 1.7 years, but one brave soul was monitored for 6.8 years (that’s a lot of swabbing, poking and prodding).

After analyzing millions of data points, the work suggests that humans don’t age in a linear fashion over time, gradually running out of juice like a flashlight with the light turned on, but rather we have two big bumps when markers associated with aging accelerate: one around age 44 and the other around age 60. The authors recognized that the average age of menopause is 45-55 and initially wondered if women in menopause were affecting the results of the group, creating a bump that looked age-related, but was really menopause transition-related. However, when analyzed separately, they found the same results for women vs. men. Meaning, menopause did not account for any differences at age 44.

Fascinating!

The study found that the first wave of age-related changes in the mid-forties included changes in molecules linked with cardiovascular disease, lipids, muscle and skin aging, and the ability to metabolize caffeine and alcohol. The second wave at age 60 involved changes in molecules that are involved in immune regulation, muscle and skin aging, carbohydrate metabolism, and kidney function.

Considering the average age of the menopause transition is 45 years, this means that if these results hold (and that is a big if), the menopause transition coincides with an acceleration of aging. Here’s an example I hear a lot, women telling me that menopause wrecked their ability to drink alcohol, but based on this information, is it menopause or is it aging? It’s something to think about and reinforced that we need to be vigilant about what we ascribe to menopause and what we ascribe to aging.

I know there are people on social media with lists of 100 or more symptoms they say are menopause, but a lot of symptoms on the list haven’t been studied rigorously, or even studied at all, and so we need to be careful. One concerning scenario that can result from incorrectly blaming a multitude of symptoms on menopause when we just don’t know, is women starting menopause hormone therapy (MHT) thinking it will help, when it may well not. Instead of stopping MHT after a trial of 3-6 months, the dose is escalated. And again and again. And then all of a sudden someone is on a massive does of estrogen, for example the equivalent of a 300 mcg patch (which is three times the average amount of estradiol during the menstrual cycle), and now when they try to stop the therapy they feel awful, because they have developed tachyphylaxis from the high doses of estrogen (you can read more about that phenomenon here).

I get concerned when I see people with large accounts being so definitive about symptoms in menopause when we are in a data-free zone. Instead, it’s really important when we don’t know, to be honest and say that, but I understand that kind of nuance doesn’t get numbers of social media.

While this study is really interesting, and should challenge us to be more open about what might be aging vs. menopause, is is important to acknowledge that it is far from definitive. The number of people enrolled is small, and the length of follow-up is rather short. While they have some longitudinal data, most of what is evaluated is essentially cross-sectional, meaning, for example, data from people aged 44 were compared with those aged 55, but we can’t assume that 44-year-olds will age like 55-year-olds, considering the massive impact of genetics and the environment on health.

This study also doesn’t rule out environmental factors as contributors—for example, an increase in alcohol consumption or a change in diet or physical activity. Studies that look at biomarkers as a surrogate for aging also need to be compared with what is happening in real life. For example, if your blood work makes you look “older,” but other metrics, like blood pressure or hand grip strength show that you are in excellent health, what does that mean?

Interestingly, this isn’t the first publication to suggest that aging isn't linear, and the timing at which things appear to accelerate in these other publications is similar to what we’ve discussed here. This tells me there is a chance there is something here, and I am really interested to see where the research takes us. We need longitudinal studies for women that can factor in these potential bumps in the trajectory of aging and sort those out from menopause, and we need more than molecular markers to capture the entirety of someone’s experience.

This paper also made me think that in addition to tracking women in menopause to see what is aging and what is menopause, it might actually be useful to have men as a control arm. I know this sounds very counter intuitive, but if we find out, for example, that men also have itchy ears in their early 50s, then perhaps that symptom is a function of aging.

I’m hearing more and more scary claims about menopause (the cynic in me has thoughts about this). For example that women lose 10% of their muscle mass in menopause or that about a third of women lose a tooth in the first five years of menopause (two claims that I have recently investigated and found lacking, check out this post on muscle and this one on tooth loss). We need to be very clear about what the science actually says and what it does not say. Rather than jumping to conclusions that may easily be incorrect, with the idea that taking swift action is better than taking the correct action, we should be pushing for and welcoming studies that can help us understand and separate out what is menopause, what is aging, and what might be the unique impacts of gender on aging for women (for example, if women have a bigger barrier to start resistance training, that might also have an impact).

There are many unanswered questions here, but that is the meandering path of science. Now that several papers have raised the question that molecular biomarkers indicate that some aspects of aging are not linear, we need to be even more careful about what we ascribe to the menopause transition vs. aging or even the environment. Otherwise, we could easily ourselves in a position where we are misleading women.

References

Shen, X., Wang, C., Zhou, X. et al. Nonlinear dynamics of multi-omics profiles during human aging. Nat Aging 4, 1619–1634 (2024). https://doi.org/10.1038/s43587-024-00692-2

Lehallier, B., Gate, D., Schaum, N. et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med 25, 1843–1850 (2019). https://doi.org/10.1038/s41591-019-0673-2