PLMI Blog

Perimenopause is a significant transitional phase marked by fluctuating estrogen and progesterone levels, resulting in alterations in metabolic, neuroendocrine, and immune pathways that influence health and well-being. These physiological shifts give rise to various symptoms, including mood changes, reduced libido, weight gain, hot flashes, and disrupted sleep. Emerging findings highlight the role of genetic variability in shaping individual susceptibility and symptom expression in perimenopause.

A 2024 review, Personalized Nutrition and Precision Medicine in Perimenopausal Women: A Minireview of Genetic Polymorphisms COMT, FUT2 and MTHFR offers compelling insight into how specific genetic variants shape the biological response to perimenopause (1). This review focuses on single nucleotide polymorphisms (SNPs) in three genes—COMT (rs4680), FUT2 (rs601338, rs602662), and MTHFR (rs1801133, rs1801131)—which play pivotal roles in neurotransmitter metabolism, gut microbiota composition, and methylation. These biological pathways are foundational to mood regulation, stress reactivity, immune balance, and cardiovascular health—domains particularly vulnerable during this transition (2).

By integrating genomic insights with nutrition and lifestyle strategies, this review highlights a paradigm shift in perimenopause that addresses restoring and optimizing underlying physiological imbalances involved.

RELEVANT GENETIC VARIANTS IN PERIMENOPAUSE

COMT rs4680: Modulating Catecholamine and Estrogen Clearance

The COMT (catechol-O-methyltransferase) gene encodes an essential enzyme that metabolizes catecholamines—dopamine, norepinephrine, and epinephrine—as well as catechol estrogens through methylation. The common rs4680 SNP (Val158Met) involves a valine-to-methionine substitution at codon 158, reducing enzyme activity by approximately 25–40% in individuals with the Met/Met genotype (3). This reduction prolongs the synaptic presence of catecholamines, enhancing dopamine availability in the prefrontal cortex, which can affect emotional regulation and increase susceptibility to mood disorders over time (4).

In perimenopause, this variant holds particular relevance. Reduced enzymatic clearance of catecholamines and estrogens can increase the brain’s reactivity to stress, increasing vulnerability to anxiety, mood lability, and sleep disruption—symptoms already exacerbated by hormonal alterations. While elevated dopamine may temporarily support cognitive performance, it can also heighten neuroinflammatory responses and oxidative stress due to metabolite accumulation, especially in the context of declining estrogen, which exerts inherent antioxidant properties (5).

From a metabolic perspective, impaired COMT activity affects neurotransmitter balance and the detoxification of reactive estrogen metabolites. Accumulation of these genotoxic intermediates (4-OH and 2-OH catechol estrogens) has been implicated in DNA damage and increased risk for estrogen-sensitive cancers. Chronic catecholamine elevation may further dysregulate the hypothalamic-pituitary-adrenal (HPA) axis, promoting systemic inflammation, insulin resistance (as glucose utilization is impeded), and nutrient depletion, particularly of magnesium and zinc—cofactors essential for mitochondrial and immune function (6). Magnesium deficiency, notably, has been linked to fatigue, anxiety, and impaired thermoregulation.

Clinically, women with the Met allele may present with heightened stress reactivity, vasomotor symptoms, and fatigue, particularly if methylation capacity is compromised (7). These effects underscore the importance of personalized interventions, including methylated B-vitamins (folate, B12, B6, riboflavin) to support methylation pathways, antioxidant repletion (e.g., magnesium, glutathione precursors) to reduce oxidative burden, and stress-modulating practices to rebalance HPA axis function.

Personalizing nutritional support based on COMT genotype may improve cognitive function, estrogen detoxification, and metabolic resilience, improving quality of life during perimenopause.

FUT2 rs601338 and rs602662: Gut Microbiota, Vitamin B12, and Cortisol Crosstalk

The FUT2 (fucosyltransferase 2) gene encodes an enzyme that regulates fucosylated antigen expression on mucosal surfaces, supporting intrinsic factor function and enabling proper vitamin B12 absorption in the ileum. Two common SNPs—rs601338 and rs602662—are associated with the non-secretor phenotype, characterized by diminished expression of these antigens in the gut lumen.

Individuals homozygous for the A allele at rs601338 exhibit absent fucosylation activity, which alters the intestinal environment by impairing microbial colonization and reducing vitamin B12 absorption efficiency. This can lead to functional B12 deficiency, even in the presence of adequate dietary intake (8). Vitamin B12 plays essential roles in DNA synthesis, red blood cell formation, neurotransmitter balance, and methylation pathways; deficiency during perimenopause therefore may exacerbate fatigue and neurological symptoms.

Beyond micronutrient absorption, FUT2 polymorphisms influence the composition and resilience of the gut microbiota, which has downstream effects on cortisol metabolism via the gut-brain axis (9). In perimenopausal women, this polymorphism may exert amplified effects, as the hormonal fluctuations of menopause independently alter gut microbiota composition (10).

Disruptions in the microbiome can impede regulation of the hypothalamic-pituitary-adrenal (HPA) axis, heightening the stress response while increasing susceptibility to anxiety, mood fluctuations, and sleep disturbances during perimenopause (11). Cortisol fluctuation may also contribute to abdominal adiposity, insulin resistance, and systemic inflammation, compounding metabolic and immune shifts already in flux due to hormonal decline.

Women who carry FUT2 variants associated with reduced secretor status may benefit from bioavailable B12 supplementation (such as methylcobalamin or adenosylcobalamin), particularly when methylmalonic acid (MMA) is elevated or neurologic symptoms are evident. Probiotic and prebiotic interventions tailored to secretor status may help restore gut barrier integrity and microbial diversity, indirectly supporting HPA axis function. Adaptogenic support and microbiome-targeted strategies may enhance cortisol resilience, buffering against stress.

By recognizing how FUT2 variants shape nutrient absorption, microbial ecology, and endocrine function, clinicians can intervene more effectively to support energy metabolism, immune regulation, and emotional balance during perimenopause.

MTHFR rs1801133 and rs1801131: Folate Cycle, Methylation, and Hormonal Balance

The MTHFR (methylenetetrahydrofolate reductase) gene encodes a critical enzyme in the folate cycle, responsible for converting 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF)—the biologically active form of folate used to remethylate homocysteine into methionine (12-13). This remethylation step is essential for maintaining methyl group availability, supporting numerous physiological functions including DNA repair, neurotransmitter synthesis, cellular detoxification, and estrogen metabolism. Two common polymorphisms in MTHFR—rs1801133 (C677T) and rs1801131 (A1298C)—have been widely studied for their impact on enzyme efficiency. Individuals homozygous for the T allele at rs1801133 can experience up to a 70% reduction in MTHFR activity, resulting in compromised homocysteine clearance, inflammation, and disrupted methylation dynamics (14).

In the context of perimenopause, this genetic variation exerts notable relevance. Declining estrogen levels already predispose women to cardiovascular and cognitive vulnerabilities, and elevated homocysteine levels may further exacerbate these risks by promoting endothelial dysfunction, oxidative stress, and systemic inflammation (15). Inadequate remethylation also affects the synthesis of mood-regulating neurotransmitters (serotonin, dopamine, and norepinephrine) contributing to common perimenopausal complaints including irritability, low mood, mental fatigue, and poor stress resilience.

Beyond its influence on mood and vascular health, methylation also plays a central role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Efficient methylation is required for the neuroendocrine stability that governs cortisol production and feedback signaling. In women with MTHFR polymorphisms, poor methylation may contribute to cortisol volatility, impairing the body’s stress response during a time when hormonal flux already challenges HPA axis integrity. This may manifest as heightened emotional reactivity, poor sleep, and vulnerability to anxiety or burnout.

Methylation also governs estrogen clearance via conjugation pathways in the liver. When MTHFR activity is impaired, this process may be delayed, prolonging estrogen receptor activation and potentially increasing susceptibility to estrogen dominance, endometrial hyperplasia, or hormone-sensitive cancers. These risks are especially relevant in individuals with concurrent impairments in COMT or CYP1B1 function.

From a precision health perspective, supporting methylation biochemically and metabolically is a hallmark of intervention. Supplementation with active folate (L-5-MTHF), methylcobalamin, riboflavin (B2), pyridoxal-5-phosphate (B6), and cofactors such as magnesium and choline, can help to optimize methylation capacity. Monitoring homocysteine, methylmalonic acid (MMA), and the SAMe-to-SAH ratio provides insight into functional status. Targeted support for neurotransmitter balance and HPA axis regulation—using interventions such as SAMe, phosphatidylcholine, or adaptogens—may further support mood and energy. For women with estrogen metabolism challenges, enhanced methylation support also helps facilitate efficient detoxification, reducing the burden of hormonal imbalance (16).

Understanding MTHFR variants allows clinicians to address underlying contributing causes of metabolic and neuroendocrine dysregulation, allowing for more efficient interventions during the perimenopausal transition.

Integrative Genomics: How These SNPs Interact

While COMT, FUT2, and MTHFR polymorphisms are often considered in isolation, their true clinical relevance emerges in their convergence across shared metabolic and neuroendocrine pathways. These single nucleotide polymorphisms (SNPs) function not as isolated variants, but as components of an interconnected and dynamic biochemical network that becomes increasingly susceptible to dysregulation during the hormonal and metabolic alterations of perimenopause (1).

COMT and MTHFR both depend on an adequate supply of methyl donors to maintain function. When variants in both genes are present, the combined impact may significantly compromise methylation efficiency, resulting in catecholamine accumulation and increased neuroinflammatory load, which can further exacerbate stress intolerance and fatigue, while exhausting methyl reserves required for DNA repair, neurotransmitter synthesis, and detoxification.

Similarly, polymorphisms in FUT2 and MTHFR can synergistically disrupt vitamin B12 and folate metabolism, which are essential cofactors in the methylation cycle. Impaired absorption of these nutrients, particularly in non-secretors with reduced FUT2 function, can further suppress homocysteine clearance and methylation stability. The resulting biochemical cascade may contribute to persistent cognitive fog, mood dysregulation, and increased cardiovascular risk.

COMT and FUT2 also intersect in their modulation of cortisol metabolism via the gut-brain-adrenal axis. Dysregulation of cortisol rhythms, due to impaired catecholamine breakdown (COMT) or altered microbial signaling and HPA feedback (FUT2), can destabilize circadian rhythms, promote central adiposity, and disrupt glucose homeostasis. These changes can further compound emotional and cognitive symptoms in perimenopausal women.

The cumulative effect of these polymorphisms is not subtle; these variants alter core physiological pathways, increasing susceptibility to chronic low-grade inflammation, mitochondrial dysfunction, oxidative stress, neurotransmitter dysregulation, and disruption of HPA axis stability. When combined with the hormonal shifts of perimenopause, these genetic variants can heighten susceptibility to various health conditions.

This review highlights how emerging machine learning technologies are accelerating the integration of genomics into personalized medicine, allowing for the creation of nutrigenomic protocols that directly address individual genetic susceptibilities.

A Functional Approach to Perimenopause

Integrating genomic insights allows for personalized, upstream interventions that aim to restore balance in the body by optimizing physiological responses during perimenopause and correcting nutritional deficiencies. Lifestyle approaches are also pivotal in supporting a woman in this transition. Improving sleep and circadian rhythm balance, engaging in regular exercise, being connected to nature, and having supportive relationships are all valuable, as are mind-body approaches for addressing stress—including yoga, meditation, and mindfulness.

Join us for our upcoming webinar on June 24, Understanding Hormonal Imbalances in Women: Symptoms, Health Impacts, and Integrative Approaches, from 5-7 PM, where leading experts Felice Gersh, MD, Malisa Carullo, BSc, MSc, ND, and Jeffrey Bland, PhD, will explore these genomic insights further, providing actionable frameworks for clinical practice.

References:

1. Andrade P, Santamarina AB, de Freitas JA, Marum ABRF, Pessoa AFM. Personalized nutrition and precision medicine in perimenopausal women: A minireview of genetic polymorphisms COMT, FUT2, and MTHFR. Clinics (Sao Paulo). 2024 Dec 5;80:100549. doi: 10.1016/j.clinsp.2024.100549. PMID: 39642577; PMCID: PMC11664282.
2. Goetz LH, Schork NJ. Personalized medicine: motivation, challenges, and progress. Fertil Steril. 2018 Jun;109(6):952-963. doi: 10.1016/j.fertnstert.2018.05.006. PMID: 29935653; PMCID: PMC6366451.
3. Pandolfo G, Gugliandolo A, Gangemi C, et al. Association of the COMT synonymous polymorphism Leu136Leu and missense variant Val158Met with mood disorders. J Affect Disord. 2015;177:108–113. doi: 10.1016/j.jad.2015.02.016. [DOI] [PubMed] [Google Scholar]
4. Dean B, Parkin GM, Gibbons AS. Associations between catechol-O-methyltransferase (COMT) genotypes at rs4818 and rs4680 and gene expression in human dorsolateral prefrontal cortex. Exp Brain Res. 2020;238(2):477–486. doi: 10.1007/s00221-020-05730-0. [DOI] [PubMed] [Google Scholar]
5. Andersen S, Skorpen F. Variation in the COMT gene: Implications for pain perception and pain treatment. 2009;10(4):669–684. doi: 10.2217/pgs.09.13. [DOI] [PubMed] [Google Scholar]
6. Serrano JM, Banks JB, Fagan TJ, et al. The influence of Val158Met COMT on physiological stress responsivity. 2019;22(2):276–279. doi: 10.1080/10253890.2018.1553949. [DOI] [PubMed] [Google Scholar]
7. Minlikeeva AN, Browne RW, Ochs-Balcom HM, et al. Single-nucleotide polymorphisms and markers of oxidative stress in healthy women. PLoS One. 2016;11(6):1–10. doi: 10.1371/journal.pone.0156450. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Hazra A, Kraft P, Selhub J, et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet. 2008;40(10):1160–1162. doi: 10.1038/ng.210. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Ferrer-Admetlla A, Sikora M, Laayouni H, et al. A natural history of FUT2 polymorphism in humans. Mol Biol Evol. 2009;26(9):1993–2003. doi: 10.1093/molbev/msp108. [DOI] [PubMed] [Google Scholar]
10. Peters BA, Lin J, Qi Q, et al. Menopause Is Associated with an Altered Gut Microbiome and Estrobolome, with Implications for Adverse Cardiometabolic Risk in the Hispanic Community Health Study/Study of Latinos. mSystems. 2022;7(3):1–18. doi: 10.1128/msystems.00273-22. [DOI] [PMC free article] [PubMed] [Google Scholar
11. Turpin W, Bedrani L, Espin-Garcia O, et al. FUT2 genotype and secretory status are not associated with fecal microbial composition and inferred function in healthy subjects. Gut Microbes. 2018;9(4):357–368. doi: 10.1080/19490976.2018.1445956. [DOI] [PMC free article] [PubMed] [Google Scholar]
12. Levin BL, Varga E. MTHFR: addressing genetic counseling dilemmas using evidence-based literature. J Genet Couns. 2016;25(5):901–911. doi: 10.1007/s10897-016-9956-7. [DOI] [PubMed] [Google Scholar]
13. De Martinis M, Sirufo MM, Nocelli C, et al. Hyperhomocysteinemia is associated with inflammation, bone resorption, vitamin b12 and folate deficiency and mthfr c677t polymorphism in postmenopausal women with decreased bone mineral density. Int J Environ Res Public Health. 2020;17(12):1–15. doi: 10.3390/ijerph17124260. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Zarembska E, Ślusarczyk K, Wrzosek M. The implication of a polymorphism in the methylenetetrahydrofolate reductase gene in homocysteine metabolism and related civilisation diseases. Int J Mol Sci. 2024;25(1):1–31. doi: 10.3390/ijms25010193. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Liew SC, Das Gupta E. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015;58(1):1–10. doi: 10.1016/j.ejmg.2014.10.004. [DOI] [PubMed] [Google Scholar]
16. Pavlik R, Hecht S, Noss U, et al. Reduced steroid synthesis in the follicular fluid of MTHFR 677TT mutation carriers: effects of increased folic acid administration. Geburtshilfe Frauenheilkd. 2022;82(10):1074–1081. doi: 10.1055/a-1791-9358. [DOI] [PMC free article] [PubMed] [Google Scholar]