A paper just published in the journal Climacteric will change the way we think about perimenopause — and I want to share it with you, because it validates something I see in my patients every single day.
The paper, by Rey and Carpintero, proposes that perimenopause should be understood as a critical neuro-musculoskeletal window. What that means is that your brain, your bones, and your muscles are all simultaneously vulnerable during the perimenopause transition — not because of three separate problems, but because of one shared set of biological drivers. The authors call this the bone-brain-muscle axis, and I think it is one of the most useful frameworks we have had in this field in years.
What Is the Bone-Brain-Muscle Axis?
As estradiol declines, FSH rises, and progesterone falls during perimenopause, the body does not respond to those hormonal shifts in a tidy, linear way. Those changes trigger a cascade of downstream effects: chronic low-grade inflammation, mitochondrial dysfunction, altered body composition, sleep disruption, and reduced physical activity. And all of those effects hit your bone, your brain, and your muscle at the same time, through overlapping, interacting pathways.
This is not coincidence. It is mechanism. The same inflammatory cytokines: CRP, IL-6, TNF-alpha, that damage bone microarchitecture are also affecting muscle protein synthesis and neurocognitive function. The same mitochondrial disruption that reduces your physical performance is also reducing energy metabolism in the brain. These systems are biologically linked, which is why so many women in perimenopause feel like everything is falling apart at once. Because physiologically, it is.
What Is Actually Happening and When
One of the most valuable parts of this paper is the timeline it lays out. Most women and most clinicians think of perimenopause as a transition that leads to problems, something to manage on the way to menopause. This paper argues that the damage is already beginning in early perimenopause, before most women even know they are in it.
In early perimenopause, when cycles are just starting to become irregular and hormones are fluctuating rather than declining steadily, subjective cognitive complaints like brain fog and memory inefficiency may already be emerging. Muscle protein synthesis is already beginning to decline. Bone turnover is already increasing, even though bone mineral density on a DEXA scan is usually still preserved. That is a critical distinction: the DEXA may look normal while the underlying microarchitecture is already changing.
By late perimenopause, all three systems are accelerating simultaneously. Cognitive symptoms become more persistent, with measurable changes in verbal memory and executive function in some women. Progressive sarcopenia is emerging, meaningful loss of muscle mass, strength, and power. Bone loss is now accelerating at both the trabecular and cortical level, with microarchitectural deterioration that increases fracture risk even before a woman reaches a clinical osteoporosis diagnosis.
The authors are clear: late perimenopause is the highest-yield window for intervention. Not postmenopause. Not when the fracture happens or the sarcopenia is established. Now, while the systems are still responding.
The Evidence: What We Know and What We Are Still Learning
The paper is a narrative review, not a clinical trial, and the authors are transparent about where the evidence is strong and where it is not.
For bone, the evidence is high quality. We have robust data showing that estrogen suppresses bone resorption, that bone loss begins before the final menstrual period, and that menopausal hormone therapy is effective for bone protection when started at the right time.
For muscle, the evidence is moderate to high. Estrogen plays a role in muscle protein synthesis and physical performance, and the decline in both during perimenopause is well documented. The mechanisms are still being characterized, but the clinical pattern is consistent.
For brain, the evidence is the most heterogeneous of the three. Subjective cognitive complaints: brain fog, forgetfulness, difficulty concentrating, are very commonly reported and are real. Objectively measured cognitive changes on neuropsychological testing are more modest and less consistent across studies. Brain fog in perimenopause is not early dementia, and the paper is careful to say that. The authors do not support using menopausal hormone therapy for primary prevention of cognitive decline. However, they do note that treating vasomotor symptoms and sleep disturbance, both of which MHT addresses effectively, may have meaningful indirect benefits for cognitive function.
What We Do at The Lee Clinic
This paper validates an approach we have been taking with our patients for years: we do not wait. The window of opportunity is during perimenopause, before the last period, and that is when we intervene.
Perimenopause often begins in the mid to late 30s and extends for years before the final menstrual period. It is a clinical diagnosis, not a blood test diagnosis, based on symptoms and cycle pattern. And the symptoms that bring women to my practice are often exactly the ones this paper describes: brain fog, fatigue, changing body composition, joint pain, sleep disruption, declining strength. These are not separate complaints. They are expressions of the same underlying hormonal transition.
When a patient comes to me in early perimenopause, I am not waiting for a dramatic hormone drop before we act. In early transition, when progesterone is often the first hormone to become insufficient, we frequently start with progesterone support: oral micronized progesterone at bedtime for sleep and mood, or a compounded cream for daytime symptoms. We address foundational nutrition: vitamin D, omega-3s, methylated B vitamins, magnesium. We talk about resistance training and protein intake, because the data on muscle protein synthesis decline starting in perimenopause means that "I'll start lifting when I'm older" is already too late for some women.
As the transition progresses and estradiol begins to decline, we layer in estradiol: transdermal gel or patch, titrated to symptom control and labs. We monitor and adjust, because hormone needs keep shifting as a patient moves through the transition. This is not a set-it-and-forget-it regimen. FSH rises, estradiol falls, and what worked two years ago may need to be retitrated.
For bone specifically, we screen early and act early. Bone microarchitecture is changing before the DEXA shows it, which means waiting for a DXA to trigger concern is not always the right approach. Weight-bearing exercise, calcium through diet, vitamin D optimization, and hormone therapy when clinically indicated, all of this matters most during the window this paper describes.
For muscle, resistance training is non-negotiable in my practice. The evidence on muscle protein synthesis decline in perimenopause means that building and maintaining muscle mass during this window has long-term consequences for falls risk, fracture protection, and independence. Adequate protein intake, most of my perimenopausal patients are significantly underconsuming protein, is a conversation we have at every visit.
For brain, treating the symptoms that drive cognitive dysfunction, sleep disruption, vasomotor symptoms, mood instability, is where we can make the most impact right now. Estrogen does not appear to prevent cognitive decline when started late, but optimizing hormone levels during perimenopause, treating sleep, and reducing the inflammatory burden of uncontrolled symptoms is what we can do, and we do it.
The Takeaway
Perimenopause is not just a reproductive transition. It is a biological window during which your brain, bones, and muscles are simultaneously vulnerable, driven by the same hormonal instability, the same inflammation, the same mitochondrial disruption. The research now supports what many of us have been seeing clinically for years: the time to intervene is not when the damage is done. It is now, before your last period.
If you are in your late 30s or 40s and you are experiencing brain fog, changing body composition, joint pain, sleep disruption, or fatigue — these are not separate problems. They may be early signs of the perimenopause transition, and they deserve a clinical evaluation and a proactive plan.