n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review
1.1. Menopause as a Delicate Phase of Women Life
- Menopause: “the permanent cessation of menstruation resulting from loss of ovarian follicular activity”;
- Perimenopause (or climacteric or menopausal transition): “the period immediately prior to the menopause (when the endocrinological, biological and clinical features of approaching menopause commence) and at least the first year after the menopause”;
- Postmenopause: the period “from the menopause, although it cannot be determined until after a period of 12 months of spontaneous amenorrhea has been observed”.
- Mind-body practices: hypnosis, cognitive-behavioral therapy, relaxation, biofeedback, meditation, and aromatherapy, mindfulness;
- The use of natural products: herbs, vitamins, minerals, and dietary supplements.
1.2. n-3 PUFA Dietary Intake
2. Materials and Methods
2.2. Search Strategy and Study Selection
2.3. Inclusion and Exclusion Criteria
- P (population): “women in menopausal transition and ovariectomized rodents”;
- I (intervention): “n-3 PUFA dietary intake and n-3 PUFA supplementation”;
- C (comparators): “control group and placebo”;
- O (outcome): “emotional and cognitive outcomes”;
- S (study design): “observational studies, clinical and preclinical trials”.
2.4. Data Extraction
3.1. Selected Studies
3.2. Effects of n-3 PUFA on Anxiety
3.3. Effects of n-3 PUFA on Depression
3.4. Effects of n-3 PUFA on Cognition
4.1. n-3 PUFA and Anxiety
4.2. n-3 PUFA and Depression
4.3. n-3 PUFA and Cognition
4.4. n-3 PUFA and Biochemical Parameters
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Article||Main Topic||Study Design||Age-Strain||Ovariectomy||n-3 PUFA Treatment Details|
|Dornellas et al. ||Anxiety and Depression||Preclinical study||8 weeks old;|
|X||Fish Diet: standard chow enriched with fish oil. The high-fat diets were prepared by adding, to the standard chow, 20% (w/w) fish oil, 20% (w/w) casein, 10% (w/w) sucrose, and 0.02% (w/w) butylated hydroxytoluene; duration: 8 weeks.|
|Wu et al. ||Anxiety and Depression||Preclinical study||12 weeks old;|
Sprague Dawley Rats
|X||Refined fish oil administrated daily by gavage (1.5 g/kg, approximately 340 mg/g for EPA, 240 mg/g for DHA); duration: 10 weeks.|
|Da Rocha et al. ||Anxiety and Depression||Preclinical study||8 weeks old;|
|X||Supplementation performed 20 days before and 20 days after the surgical procedure: daily dose of 500 mg/kg/day of omega-3 (1000 mg capsules, containing 180 mg of EPA and 120 mg of DHA); duration: 40 days.|
|Jin et al. ||Depression||Preclinical study||3 weeks old;|
(after 8 weeks of supplementation)
|The diets were isocaloric and modified with 0%, 1% or 2% EPA + DHA relative to the total energy intake (0 g, 8.09 g and 16.21 g of fish oil per kg of diet, respectively).|
The diets contained 10% of total energy from fat, with 42.94 g/kg diet of fish oil and grape seed oil; duration: 12 weeks.
|Choi et al. ||Depression||Preclinical study||3 weeks old;|
(after 8 weeks of supplementation)
|Diets were isocaloric modified with 0% n-3 PUFA, 1% ALA, 1% EPA or 1% DHA relative to the total energy intake.|
The control diet contained 70 g/kg of grape seed oil; the ALA, EPA and DHA diets contained 8.27 g/kg of flaxseed oil, 4.46 g/kg of EPA EE and 4.67 g/kg of DHA EE, respectively.
The control diet had 0.05% of n-3 PUFA, and the ALA, EPA and DHA diets had 6.40% of ALA, 6.35% of EPA and 6.35% of DHA in total fatty acids, respectively; duration: 12 weeks.
|Konuri et al. ||Cognition||Preclinical study||9–10 months;|
|X||Choline (4.6 mmol/kg/day) in combination with DHA (300 mg/kg/day); duration: 30 days.|
|Article||Behavioral Tests||Biochemical Analyses||Behavioral Results||Biochemical Results|
|Dornellas et al. ||EPM; FST Modified.||No Biochemical Analyses were performed.||High fat diet had an anxiolytic effect regardless the fatty acid composition.|
No differences were found in depressive-like behaviors.
|In the hippocampus, fish oil diet induced a stimulation in the serotoninergic activity, which is expressed in an increase in 5-hydroxyindoleacetic acid levels and in serotonergic turnover.|
|Wu et al. ||EPM; FST; Sucrose Preference Test; Novelty Suppressed Feeding Test.||Hormone Assay: ELISA Kit for E2;|
Apoptosis analysis: terminal deoxynucleotidyl transferase-mediated FITC-dUTP nick end labelling (Tunel) method;
Microglia activation: Immunostaining of Iba-1;
Cytokine Expression and Microglia Polarization:
Western blot analysis of phosphorylation of NF-κB pp65, p65, IκB, iNOS, Arg-1 and β-actin; RT-PCR analysis.
|n-3 PUFA supplementation:|
reverted the OVX induced anxiety-like behaviors displaying notable anxiolytic properties;
alleviated OVX induced depressive-like behaviors in the FST and NSFT.
|n-3 PUFA supplementation increased:|
IL-10; IL-4; IκB; p65.
n-3 PUFA supplementation decreased:
IL-1β; IL-6; NFκB;
n-3 PUFA supplementation ameliorated:
microglia activation; neuronal apoptosis.
|Da Rocha et al. ||EPM; FST; Open Field.||Thiobarbituric acid reactive substances and catalase in the brain tissue;|
Glutamate in the cerebrospinal fluid.
|The n-3 PUFA supplementation had an anxiolytic effect increasing the locomotory activity in the OF.|
The depression-like behavior was improved in the FST.
No differences between groups were found in the EPM.
|n-3 PUFA supplementation did not had any effect on Thiobarbituric acid reactive substances, catalase and glutamate.|
|Jin et al. ||FST.||Gas chromatography for the fatty acid composition of the brain tissue;|
Brain tissue levels of PGE2;
Immunofluorescence staining for ER-α and ER-β;
Blood samples collection to measure:
serotonin serum levels; plasma
Hippocampal Western blot analysis of:
CREB; pCREB; TNF-α; BDNF; IL-1β, IL-6; ER-α or ER-β.
|n-3 PUFA supplementation increased climbing and decreased immobility and had no significant effects on duration of swimming.||n-3 PUFA supplementation increased:|
serum serotonin concentrations; the brain phospholipid level of n-3 PUFA (20:5n3, 22:5n3 and 22:6n3) in a dose-dependent manner; expression of CREB (among 0% vs. 1% and 0% vs. 2%); expression of BDNF (among 0% vs. 2% and 1% vs. 2%); expression of ER-α (among 0% vs. 1% and 0% vs. 2%).
n-3 PUFA supplementation decreased:
PGE2 brain levels; brain phospholipid level of n-6 PUFA (20:4n6, 22:4n6 and 22:5n6) in a dose-dependent manner; TNF-α (among 0% vs. 2% and 1% vs. 2%); IL-6 (among 0% vs. 1% and 0% vs. 2%).
|Choi et al. ||FST.||Gas chromatography for the fatty acid composition of the brain tissue;|
Plasma analysis for estrogens and malondialdehyde levels; Brain tissue levels of PGE2; Immunofluorescence staining for BDNF levels in DG.
Serum analysis for: serotonin; NOx; superoxide dismutase levels.
Hippocampal Western blot analysis for: CREB; pCREB; BDNF; TNF-α; IL-6; ER-α or ER-β.
In vivo magnetic resonance imaging/spectroscopy of the left dorsal hippocampal region to calculate peak concentrations of: creatine; phosphocreatine; glucose; glutamate; myo-inositol.
|Supplementation with EPA and DHA, but not ALA, decreased the duration of immobility by 49%, and increased climbing by 69%.||Supplementation with:|
ALA increased brain phospholipid proportion of 18:3n3 as compared to the control, EPA and DHA diet.
ALA, EPA and DHA increased the brain phospholipid proportions of 20:5n3, 22:5n3 and 22:6n3, this increase was greater with EPA and DHA than ALA supplementation.
ALA, EPA and DHA decreased the brain phospholipid proportions of 18:2n6, 20:4n6, 22:4n6 and 22:5n6 and the decrease of proportions of 20:4n6, 22:4n6 and 22:5n6 were greater with of EPA and DHA than with ALA.
EPA and DHA, increase serum serotonin levels by 29%.
EPA and DHA decreased: PGE2 brain levels by 37%; serum concentrations of NOx by 52%; TNF-α expression by 26%; IL-6 expression by 29%.
EPA and DHA increased hippocampal expression: hippocampal expression of ER-α by 21%; CREB by 34%; pCREB by 56%; BDNF by 32%.
|Konuri et al. ||Eight-arm radial maze test;||Right cerebral hemisphere BDNF analysis using ELISA kit.|
E2 serum levels measured with ELISA kit.
Golgi-Cox staining of the left cerebral hemisphere to evaluate dendritic arborization and length.
|The dietary supplementation of choline-DHA significantly improved the memory retention.||The dietary supplementation of choline-DHA:|
Increase BDNF levels; improved basal and apical dendritic branching points and dendritic intersections in CA1 and CA3;
Did not show any effect on serum E2 concentration.
|Cohen et al. ||Menopause transition: amenorrhea ≥60 days in the past year|
Postmenopause: ≥12 months since last menstrual period or bilateral oophorectomy
Hysterectomy: with follicle stimulating hormone >20 mIU/mL and estradiol of ≤50 pg/mL
|Lucas et al. ||Postmenopausal status: 12 months of amenorrhea after the final menstrual period|
|Freeman et al. ||Peri- Post- menopause: Women that met perimenopause or postmenopause status as defined by the standardized Stages of Reproductive Aging Workshop criteria|
|Persons et al. ||Postmenopause: not specified by authors.|
|Jin et al. ||Menopause: not specified by authors.|
|Masoumi et al. ||Postmenopause: at least 12 months of amenorrhea.|
|Colangelo et al. ||Postmenopause: Women were classified as postmenopausal if (a) they responded ‘yes’ to the question, ‘Have you gone through menopause (change of life)?’, or (b) had a prior hysterectomy and bilateral oophorectomy.|
|Li et al. ||Early Perimenopause: menstrual bleeding in the past 3 months accompanied by changes in cycle regularity.|
Premenopause: menstrual bleeding in the past 3 months with no change in cycle regularity in the past 12 months.
|Chae and Park ||Menopause: not specified by authors.|
Postmenopause: not specified by authors.
|Ammann et al. ||Postmenopause: not specified by authors.|
|Strike et al. ||Postmenopause: not specified by authors.|
|Article||Main Topic||Study Design||Sample Size and Age (Years)||Ethnicity||Exclusion Criteria|
|Cohen et al. ||Anxiety and Depression||Randomized Controlled Trial||n = 355|
|White; African American; Other||Body Mass Index > 37; use of hormones or hormonal contraceptives in the past 2 months; use of prescription or over-the-counter treatments for vasomotor symptoms in the past month; any unstable medical conditions; contraindications to exercise training, yoga, or omega-3; current participation in regular exercise or yoga; current use of omega-3 supplements or frequent consumption of fish; MDE in the past three months.|
|Lucas et al. ||Depression||Randomized Controlled Trial||n = 120|
|White||Severe MDE [scores of 26 on HAM-D-21]; history of schizophrenia or bipolar I and II disorder; imminent risk of suicide or homicide; |
postmenopausal status for >5 years; medical conditions that affect mental health; substance abuse or dependence; fish allergies; high fish consumption (>3 servings/week) in the past 3 months; use of antidepressants; hormone replacement therapy; fish-oil supplements in the past 3 months; anticoagulants use.
|Freeman et al. ||Depression||Open-Label Trial||n = 19|
Age mean: 52.5 ± 4.9
|Caucasian; African American; Other||Currently pregnant, breast-feeding, or trying to conceive; currently being treated with an antidepressant, hormone treatment, or n-3 PUFA supplements or with one of the preceding treatments within 1 month of study entry; suicidal ideation; current or recent (past month) diagnosis of panic disorder or obsessive-compulsive disorder or history of psychosis, mania, or hypomania, as assessed by the MINI, diagnosis of treatment-resistant Major Depressive Disorder; fish or fish oil allergies;|
responded to placebo [950% decrease in the MADRS].
|Persons et al. ||Depression||Retrospective Cohort Study||n = 7086|
|Not specified||Not Specified.|
|Jin et al. ||Depression||Cross-Sectional Study||n = 214|
Age: from 54.23 ± 5.43 to 56.02 ± 6.09
|Masoumi et al. ||Depression||Randomized Controlled Trial||n = 60|
|Not specified||Depression scores higher than 30 at follow-ups and any known drug side effects.|
|Colangelo et al. ||Depression||Retrospective Cohort Study||n = 1616|
|Non-Hispanic White; African American; Chinese American; Hispanic||Not Specified.|
|Li et al. ||Depression||Cross-Sectional Study||n = 3054|
|Non-Hispanic White; Chinese; Japanese; Hispanic; Black||No intact uterus or ovaries; use of reproductive hormones and amenorrhea in the previous 3 months.|
|Chae and Park ||Depression||Cohort Study||n = 4150|
Age: from 62.8 ± 0.3 to 67.1 ± 0.3
|Korean||Men; pregnant, lactating, or premenopausal women; |
women with a total energy intake of less than 500 kcal or more than 5000 kcal/day; women with no data on depression.
|Ammann et al. ||Cognition||Retrospective Cohort Study||n = 2157|
|Strike et al. ||Cognition||Randomized, Double-Blind,|
Placebo-Controlled Pilot Study
|n = 27|
|English||Vestibular impairments; neurological disorder; lower limb surgery; |
allergy to seafood; regular consumption of multivitamin/fish oil supplements.
|Article||Main Topic||n-3 PUFA Treatment Details||Behavioral Analyses||Biochemical Analyses||Main Results|
|Cohen et al. ||Anxiety and Depression||1.8 g/day|
(3 pills/day, each containing 425 mg of EPA, 100 mg DHA and 90 mg of other omega-3) for 12 weeks.
|Physician’s Health Questionnaire-8 (depression domains); Generalized Anxiety Disorder Questionnaire-7.||No Biochemical Analyses were performed.||n-3 PUFA did not improve mood over placebo.|
|Lucas et al. ||Depression||3 capsule/day containing 350 mg EPA and 50 mg DHA in the form of ethyl esters for 8 weeks.||MINI (version 5.0.0); Psychological General Well-Being Schedule; 20-item Hopkins Symptom Checklist Depression Scale; HAM-D-21; Clinical Global Impression Severity Scale; FFQ (based on marine products).||RBCs fatty acid |
|Ethyl-EPA treatment over placebo improved significantly psychological distress and depressive symptoms in women without MDE.|
|Freeman et al. ||Depression||2 g/day (2 capsules per day each 1-g capsule contains 840 mg of the EE of n-3 PUFA, as a combination of EE of EPA (approximately 465 mg per capsule) and DHA (approximately 375 mg per capsule)) for 8 weeks.||MINI for the diagnosis of Major Depressive Disorder; MADRS.||RBCs fatty acid |
|Significant decrease in MADRS scores after treatment.|
|Persons et al. ||Depression||No treatment has been used in this study.||Burnam 8-item scale for depressive disorders: combined CES-D/DIS short form.||RBCs fatty acid |
|Positive association between: RBC n-3 PUFA levels (DHA, both EPA + DHA and total n-3 PUFA) and depressive symptoms (the effect disappeared after adjusting data for demographic and health behavior characteristics); n-3 PUFA dietary intake (total n-3 PUFA, DHA, and DHA + EPA) with a higher prevalence of depressive symptoms; the risk to develop depressive symptoms and total n-3 PUFA (in the follow-up analysis, after excluding prevalent cases of depression in baseline).|
|Jin et al. ||Depression||No treatment has been used in this study.||BDI; Medical Records to assess at least 3 HT use; Interviews to assess dietary intake and general information.||No Biochemical Analyses were performed.||Significant negative correlation between Erythrocyte levels of n-3 PUFA of ALA, DPA, and DHA and depression only in women using HT.|
|Masoumi et al. ||Depression||Citalopram with 1 g of n-3 PUFA for 1 week.||Diagnostic and Statistical Manual of mental disorders-IV questionnaire to assess depression; BDI.||No Biochemical Analyses were performed.||Mean depression score lower in two and four weeks after intervention.|
|Colangelo et al. ||Depression||No treatment has been used in this study.||FFQ modified; CES-D.||Blood collection for the assessment of E2.||Significant interaction of HT with n-3 PUFA intake and depressive symptoms.|
|Li et al. ||Depression||No treatment has been used in this study.||FFQ; CES-D.||No Biochemical Analyses were performed.||n-3 PUFA intake was negatively correlated with depressive symptoms in early perimenopausal but not in premenopausal women.|
|Chae and Park ||Depression||No treatment has been used in this study.||Self-reported mental health questionnaire to assess depression; 24-h phone call interview to assess dietary intake.||No Biochemical Analyses were performed.||n-3 PUFA intake in postmenopausal women was inversely proportional to depression in a dose-response manner.|
|Ammann et al. ||Cognition||No treatment has been used in this study.||Finger Tapping Test; Card Rotations Test; Benton Visual Retention Test; California Verbal Learning Test; Primary Mental Abilities (Vocabulary test); Letter and category fluency tests; Digit Span (Forward and Backward Test).||RBCs fatty acid |
|RBC DHA-EPA levels were not significantly correlated with baseline cognitive function and cognitive change over time.|
|Strike et al. ||Cognition||4 capsules/day (1 g DHA and 160 mg EPA per day in addition to Ginkgo biloba, PS, α-tocopherol, folic acid, and vitamin B12) for 24 weeks.||Cambridge Cognition Ltd.: A battery of computer-based cognitive test; MOT; VRM; Paired Associate Learning; Stockings of Cambridge.||RBCs fatty acid |
|Supplemented group had:|
shorter mean latencies in MOT;
higher number of words remembered in the VRM.
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Decandia, D.; Landolfo, E.; Sacchetti, S.; Gelfo, F.; Petrosini, L.; Cutuli, D. n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review. Nutrients 2022, 14, 1982. https://doi.org/10.3390/nu14091982
Decandia D, Landolfo E, Sacchetti S, Gelfo F, Petrosini L, Cutuli D. n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review. Nutrients. 2022; 14(9):1982. https://doi.org/10.3390/nu14091982Chicago/Turabian Style
Decandia, Davide, Eugenia Landolfo, Stefano Sacchetti, Francesca Gelfo, Laura Petrosini, and Debora Cutuli. 2022. "n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review" Nutrients 14, no. 9: 1982. https://doi.org/10.3390/nu14091982