Women's health without taboos
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Time to read 9 min
Women's Health · Perimenopause
Is it chronic fatigue
Is it chronic fatigue
or perimenopause?
What you are feeling at 40 has a neuroendocrine explanation. It's not a lack of motivation: it's biology. Here we explain it to you without taboos.
The 40s are a complex age for women. The vast majority have to pretend to be healthy, when in reality they feel tremendously exhausted physically and mentally. And to make matters worse, they follow extreme diets and training routines because what worked for them in their twenties or thirties no longer gives them the same results, and they believe they should push themselves harder at this stage.
The problem is that their metabolism, hormonal system, and mental health undergo changes that are often ignored by health professionals, where many taboos regarding women's health still persist. In this blog, we will tell you that it's not all a matter of "getting motivated" and you might not necessarily have depression or fibromyalgia, as there are neuroendocrine reasons associated with the perimenopause stage that explain the reason for the brain fog, fatigue, tiredness, and other symptoms that you may be feeling and cannot find an explanation for.
Do you go into a room and forget what you went in there for? You may be experiencing Brain Fog
Menopause occurs on average at 51 years of age, but perimenopause can begin up to 10 years earlier. During this window, a woman's ovarian reserve decreases, which causes chaotic fluctuations in steroid hormones.
🔬 Neuroendocrine mechanism
The role of 17β-estradiol in the brain
17β-estradiol is the most active form of estradiol and is a potent homeostatic neurosteroid. Among its functions, it regulates the glucose transport system (specifically the GLUT1 and GLUT3 transporters) across the blood-brain barrier and into neurons. It also optimizes mitochondrial oxidative phosphorylation for the production of adenosine triphosphate (ATP), known as our body's energy currency.
When estradiol levels fluctuate or drop, the brain experiences an energy crisis due to glucose hypometabolism. The regions with the highest density of estrogen receptors—the hippocampus (memory) and the prefrontal cortex (executive functions)—when suffering from an ATP deficit, generate short-term memory lapses and slowness in information processing.
Difficulty falling asleep
On the other hand, we have progesterone: this hormone is a precursor to allopregnanolone, a neurosteroid that acts as a potent brain calmer, regulating mood, anxiety, and stress. It is a positive modulator of GABA receptors.
🧠 The glymphatic system
Deep sleep as a brain-cleaning mechanism
GABA acts as the main inhibitory neurotransmitter of the nervous system, inducing slow-wave sleep or delta phase. During this stage, while we sleep, the glymphatic system is activated: a cleaning mechanism that pumps cerebrospinal fluid through brain tissue to remove metabolic waste, such as beta-amyloid proteins.
When a drastic drop in progesterone occurs starting at age 40, this deep sleep becomes fragmented. By losing this window of glymphatic cleaning, the brain wakes up inflamed due to the accumulation of waste, which perpetuates morning lethargy and sleepiness.
Tiredness, chronic fatigue, and slowed metabolism
All steroid hormones, both stress and sex hormones, are manufactured from the same parent molecule called pregnenolone.
From an evolutionary point of view, the body will always prioritize immediate survival over long-term functions like reproduction. For this reason, if the demand for cortisol or the "stress hormone" remains chronically elevated, whether due to physical or mental factors, the body is forced to divert its internal resources.
In moments of tension or chronic stress, our body will need large amounts of cortisol. Therefore, the enzymatic pathways hoard this parent molecule to produce it, sacrificing the production of progesterone.
This phenomenon generates a severe deficit of progesterone that ends up directly impacting the thyroid, the gland responsible for regulating metabolism. Under normal conditions, the thyroid produces T4 (inactive) which must be converted into T3 (the active form). However, excess cortisol and a lack of progesterone block this conversion process, decreasing overall thyroid function. This translates into reduced energy, a slower metabolism, and a greater feeling of generalized fatigue.
As a significant fact: hypothyroidism has a higher prevalence in women than in men.
Mistakes you should not make during the perimenopause stage
These practices, although they seem logical to combat tiredness, can significantly aggravate your symptoms:
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Abusing coffee
The use of high doses of caffeine blocks adenosine receptors—the main molecule responsible for our need to sleep—and at the same time artificially increases catecholamines (adrenaline and noradrenaline). This worsens subsequent energy crashes.
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Extreme ketogenic or strictly low-calorie diets
The perimenopausal brain perceives the absence of carbohydrates or energy as a sign of acute cellular stress. This depletes tryptophan levels, the amino acid precursor of serotonin and melatonin, increasing the permeability of the blood-brain barrier and susceptibility to anxiety.
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Excessive cardiovascular exercise (especially on an empty stomach)
High-intensity, long-duration cardio in a sleep-deprived body raises cortisol to a point where muscle catabolism (sarcopenia) is promoted. By losing muscle tissue, mitochondrial density is reduced. High cortisol destroys muscle mass, blocks the thyroid, and causes the body to accumulate fat in the abdominal area.
The Estrobolome and its relationship to women's health
🦠 Intestinal microbiota
What is the Estrobolome?
The Estrobolome is the fraction of intestinal bacteria (especially Bacteroides, Bifidobacterium, and certain families of Firmicutes) whose enzymatic products are capable of modulating systemic estrogen homeostasis.
Under normal physiological conditions, estrogens metabolized in the liver are conjugated with glucuronic acid to facilitate their excretion via bile into the intestinal lumen. The bacteria of the estrobolome encode the enzyme β-glucuronidase, which catalyzes the deconjugation of estrogens, transforming them into biologically active free estrogens that are reabsorbed into systemic circulation.
At age 40, the estrogenic decline induces changes in the composition of the microbiota. This intestinal dysbiosis decreases the activity of bacterial β-glucuronidase, which results in deficient deconjugation. Consequently, estrogens are massively eliminated through feces, depriving the body of its circulating reserve estrogen pool. This aggravates cerebral hypometabolism and accelerates neuroendocrine symptoms.
Tips for caring for the Estrobolome at this stage
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Increase fiber and prebiotics
Consume vegetables, legumes, oats, and seeds (such as flaxseed, chia) to feed beneficial bacteria.
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Add live fermented foods (unpasteurized)
Integrate sauerkraut or kimchi to diversify the microbiota naturally.
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Reduce ultra-processed foods and alcohol
These products directly damage the intestinal mucosa and the microbiota.
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Avoid unnecessary use of antibiotics
They can destroy the bacterial populations responsible for recycling hormones.
Smart (and not extreme) strategies for this stage
Incorporate healthy fats into your diet
The brain is almost 60% fat. Neurons are covered by a layer of myelin (formed by fat), which allows electrical impulses to travel quickly. If you consume everything "light" or "zero fat," the brain and its functions, such as memory, cognition, processing speed, and focus, are left unprotected.
The monounsaturated fats in extra virgin olive oil act as ligands for PPAR-gamma receptors, improving cellular insulin sensitivity and making it easier for glucose to enter the brain efficiently despite the estrogenic decline. They are the base substrate for the body to continue producing hormones.
Consume complex or whole-grain carbohydrates
It is important to end the phobia of carbohydrates. Our body needs slow-digesting ones, rich in fiber. The intake of complex carbohydrates stimulates a moderate release of insulin that promotes the cellular uptake of branched-chain amino acids (BCAAs) in skeletal muscle, leaving the way clear for tryptophan to cross the blood-brain barrier. Once in the central nervous system, tryptophan is converted into serotonin and melatonin, ensuring deep sleep.
Some examples: potato, sweet potato, whole oats, quinoa, legumes, brown rice, vegetables of all colors.
Evidence-based supplementation
Scientific evidence supports the use of the following nutrients and botanical compounds during perimenopause. Below, each category with its products available at Ortomolecular Chile:
Omega-3: EPA and DHA — Cerebral anti-inflammatory
DHA is a structural component of synaptic membranes. EPA acts as a precursor to resolvins, which inhibit NF-kB-dependent inflammatory pathways in microglia (the brain's immune cells). Omega-3 is a potent cerebral anti-inflammatory that reduces brain fog.
Recommended products · Omega-3
Cerebral magnesiums: Acetyl-taurate and Magnesium L-threonate
Both forms of magnesium stand out for their high bioavailability and their exclusive ability to cross the blood-brain barrier. Magnesium L-threonate acts directly on the central nervous system, being the primary ally against neuroinflammation, brain fog, and memory lapses. Magnesium acetyl-taurate optimizes interaction with GABA receptors, decreasing anxiety, regulating stress, and relieving menstrual migraines or the sudden mood swings typical of this hormonal transition.
Recommended products · Cerebral magnesiums
B-Complex (B6, B9, B12 as methylcobalamin)
Essential for maintaining the methylation cycle and regulating levels of homocysteine, a neurotoxic amino acid. B vitamins act as essential cofactors in the Krebs cycle within the mitochondrial matrix to optimize ATP synthesis and energy generation. They also participate in neurotransmitter synthesis and myelin synthesis.
Recommended products · B-Complex
Withania somnifera (Ashwagandha): the natural anxiolytic
The active components of ashwagandha (withanolides) mimic GABA activity and have been shown to reduce serum cortisol concentrations, which is why it is considered an effective "natural anxiolytic."
Recommended products · Ashwagandha
Probiotics specific to the gut-brain axis and Estrobolome
Strains of Lactobacillus acidophilus, Lactobacillus reuteri, and Bifidobacterium longum have demonstrated the ability to modulate colonic β-glucuronidase activity and improve estrogen recycling.
Recommended products · Probiotics by strain
Lactobacillus acidophilus
Creatine: preserves muscle and clears the mind
Traditionally associated with athletic performance, creatine helps combat the accelerated loss of muscle mass (sarcopenia) and bone density when combined with strength training. The most recent scientific evidence highlights its ability to counteract daily fatigue, stabilize mood, and clear brain fog thanks to its essential role in cellular energy production in the brain.
Recommended product · Creatine
Isoflavones: natural hormonal regulators
Isoflavones are phytoestrogens that act as highly effective natural hormonal regulators for relieving perimenopause symptoms. By having a chemical structure similar to the body's estrogens, these plant compounds bind to their receptors to compensate for hormonal decline, significantly reducing the frequency and intensity of hot flashes and night sweats. They also help slow down bone density loss and protect cardiovascular health during this biological transition.
Recommended product · Isoflavones
Conclusion: your body is not failing, it is transitioning
At 40, the female organism undergoes a biological transition that invalidates reductionist approaches based exclusively on the thermodynamic energy balance (eating less and moving more).
Treating perimenopausal symptomatology through nutritional restriction and overstimulation of the central nervous system accelerates mitochondrial failure, destroys the intestinal barrier, and nullifies the estrobolome recycling function, worsening cognitive dysfunction and brain fog.
The transition toward the cessation of ovarian function must be addressed from an integrative perspective. Replacing caloric restriction with functional nutritional density, rigorous care of the microbiota, optimization of rest through the glymphatic pathway, and the attenuation of systemic neuroinflammation constitute the molecular pillars validated by scientific evidence to dissipate brain fog, restore mitochondrial vitality, and preserve the metabolic and neurological longevity of the female organism.
Bibliography
- Plottel, C. S., & Blaser, M. J. (2011). Microbiome and malignancy: cells, molecules, and cancers. Cell Host & Microbe, 10(4), 324–335. doi.org
- Baker, J. M., Al-Nakkash, L., & Herbst-Kralovetz, M. M. (2017). Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas, 103, 45–53. doi.org
- Maki, P. M., & Thurston, R. C. (2020). Menopause and brain health: Introduction to the special issue. Menopause, 27(12), 1321–1323. doi.org
- Brinton, R. D., et al. (2015). Perimenopause as a neurological transition state of lack of energy. Frontiers in Neuroendocrinology, 38, 14–33. doi.org
- Chandrasekhar, K., Kapoor, J., & Anishetty, S. (2012). Safety and efficacy of ashwagandha root in reducing stress and anxiety. Indian Journal of Psychological Medicine, 34(3), 255–262. doi.org
- Jessen, N. A., et al. (2015). The Glymphatic System: A Beginner's Guide. Neurochemical Research, 40(12), 2583–2599. doi.org
