Omega-3 Fatty Acids and the Menopausal Transition: Clinical Efficacy in Depression and Beyond

by Leah Gillingham, PhD

Introduction

Natural menopause is defined as 12 consecutive months of amenorrhea after the final menstrual period.¹ Perimenopause, also called the menopausal transition, refers to the time period of changing ovarian function and estrogen levels occurring 2 to 8 years prior to the final menstrual period. The onset of menopause has a wide range (42–58 years) with an average age of 51 years. The prevalence of depression or mood swings; hot flashes; and joint aches, pain, and stiffness increases during the menopausal transition.² The symptoms of menopause are closely linked to the fluctuating and declining levels of estrogen and associated changes in serotonergic transmission.³ In addition, many women experience sleep disturbances, decreased libido, vaginal dryness, dry eye symptoms, and increased cardiovascular risk; namely, hypertriglyceridemia and arrhythmias. The use of complementary and alternative medicine (CAM) to improve quality of life during the menopausal transition has increased in light of the demonstrated or perceived risks of hormone replacement therapy.⁴

Considerable clinical interest has focused on the health benefits of omega-3 polyunsaturated fatty acids (PUFA), one of the most widely used dietary supplements on the CAM market. Omega-3 fatty acids are classified as essential PUFAs because they cannot be synthesized by humans and thus must be consumed in the diet. The most important bioactive omega-3 PUFAs include the long-chain forms eicosapentaenoic acid (EPA; 20:5ω-3) and docosahexaenoic acid (DHA; 22:6ω-3), predominantly found in fish and fish oils. EPA and DHA play a vital role in cellular membranes, maintaining fluidity, protein, and cellular functions, as well as influencing eicosanoid metabolism, gene expression, and cell signaling.⁵ In addition, endogenous EPA and DHA levels are associated with estrogen status and serotonin metabolism.^6–8 Therefore, this review investigates the efficacy of EPA and DHA supplementation for common symptoms of the menopausal transition.

Depression

Depression is a chronic and recurrent illness twice as prevalent in women as in men.⁹ Moreover, women are particularly susceptible to psychological distress and depressive symptoms during the menopausal transition and early menopause.¹⁰ More than 20% of women will experience a major depressive disorder during their lifetime, with 15-18% of perimenopausal women and 8% to 12% of premenopausal women affected by persistent mood symptoms.^9,11,12 Antidepressant medication effectiveness is directly correlated with the severity of depression symptoms, with minimal or no effect in patients with mild or moderate symptoms, and an observed 19% to 34% of patients failing to respond to medications.^13,14 Moreover, in the Women’s Health Initiative prospective cohort study of 136,293 community-dwelling postmenopausal women investigating antidepressant use and the risk of incident cardiovascular morbidity and mortality, selective serotonin reuptake inhibitor (SSRI) use was associated with increased stroke risk (HR = 1.45; 95% CI: 1.08–1.97) and all-cause mortality (HR = 1.32; 95% CI: 1.10–1.59), and tricyclic antidepressant use was associated with increased risk of all-cause mortality (HR = 1.67; 95% CI: 1.33–2.09).¹⁵ Considering this, CAM treatment is necessary, particularly in menopausal depression.

Observational studies reported an increased prevalence of depression associated with decreased concentrations of EPA, DHA, or both in cell membranes or plasma.^16,17 Mechanistically, incorporation of EPA and DHA in neuronal membranes decreases the reuptake rate of serotonin, similar to the effects of SSRIs.^7,8 Low plasma DHA levels have been shown to be associated with low levels of 5-hydroxytryptamine (or serotonin) and the pathophysiology of depression and impulsive behavior.¹⁸ In addition, oral estrogen therapy results in an upregulation of endogenous conversion of alpha-linolenic acid (ALA; 18:3ω-3) to DHA, resulting in increased EPA and DHA plasma concentrations, and may contribute to a role in antidepressant effects.¹⁹

In a small preliminary open trial, Freeman et al. investigated the effects of omega-3 supplementation for major depressive disorder associated with the menopausal transition.¹⁹ After 8 weeks, supplementing with 2 g/day omega-3 capsules (providing 930 mg ethyl-EPA + 750 mg ethyl-DHA daily) resulted in a 56% decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS; p < 0.0001), with 14 of 20 women having their MADRS score decrease by 50% or more. In a study of 60 outpatient men and women, supplementing 1000 mg of EPA or 20 mg fluoxetine for 8 weeks demonstrated equal therapeutic effects in major depression disorders, with response rates of 50%, 56%, and 81% in the fluoxetine, EPA, and combination (fluoxetine + EPA) groups, respectively.²⁰ A recent meta-analysis of 8 double-blind randomized controlled trials reported that the combination of EPA and DHA as monotherapy (range of EPA+DHA supplementation from 1.2 to 6.6 g/d; average daily dose of ~3 g EPA+DHA) for 8 weeks effectively treated depression in women as compared to placebo (0.65; 95% CI =0.18–1.12, p = 0.007).²¹ Of interest, 7 of the 8 studies used a higher dose of EPA than DHA (approximately 2:1 ratio of EPA:DHA in 5 of the trials).

DHA is structurally the most abundant omega-3 long-chain PUFA in the brain, comprising approximately 40% of all PUFAs in the brain. ²² Therefore, one might assume that supplementing the major structural component of neuronal membranes, being DHA, would exert the most beneficial effect on brain function and depression. However, supplementation with higher concentrations of EPA over DHA has been shown to be responsible for the efficacy of omega-3 long-chain PUFA supplementation in depression.²³ A meta-analysis by Martins et al. reported a significant reduction in depression symptoms is studies supplementing more than 50% EPA or using pure ethyl-EPA, whereas supplements containing more than 50% DHA or pure DHA were ineffective.²³ The authors proposed that the cell signaling mechanisms of EPA might explain the enhanced efficacy over DHA in depression. EPA increases the production of anti-inflammatory eicosanoids, decreases the secretion of pro-inflammatory cytokines (i.e. tumor necrosis factor(TNF)-α, interleukin(IL)-6, IL-1β) via inhibition of nuclear factor (NF)-κB, decreases mitochondrial membrane permeability, prevents cytochrome C release, and decreases neuronal apoptosis.²³

With respect to clinical efficacy, subgroup analysis by Martins et al. demonstrated improved efficacy for major depression versus mild-to-moderate depression, therapeutic versus preventative intervention, adjunctive versus monotherapy, and supplement type, with higher EPA showing significant improvements.²³ Supplements containing EPA (≥60%) in excess of DHA, with a suggested daily dose of ≥1g EPA provide optimal efficacy for primary depression,^23–25 a primary symptom of the menopausal transition.

Hot Flashes

Hot flashes, as well as night sweats, are one of the most frequent and distressing vasomotor symptoms of the menopausal transition. Hot flashes, or hot flushes, are primarily characterized by a subjective heat sensation, including sweating, cutaneous vasodilatation, increased heart rate and an associated drop in core temperature.¹ Approximately 80% of all women are affected by hot flashes, with 40% of women pursuing medical care due to the severity of symptoms.^2,3 Hot flashes are a physical symptom reflecting the brain’s sensitivity to the changes in the hormonal environment during the menopausal transition, namely the rapid decline in estrogen levels.²⁶ In addition, there is a direct correlation between women who suffer from hot flashes during the menopausal transition and a greater risk of developing a major depressive disorder.²⁷ Perimenopausal women, but not postmenopausal, experiencing vasomotor symptoms are 4.39 times more likely to be depressed than those without vasomotor symptoms (95% CI, 1.40–13.83)^{. 26} In light of potential risks of hormonal interventions² and bothersome side effects of SSRIs,²⁸ many women pursue CAM treatments for vasomotor symptoms. EPA and DHA alter serotonin transmission,^7,8 similar to that of SSRIs, and therefore may effectively reduce vasomotor symptoms, namely the frequency and intensity of hot flashes.

Campagnoli et al. first observed the beneficial effects of polyunsaturated fatty acids on hot flushes in women.²⁹ PUFA supplementation (providing 400 mg fish oil (30% EPA plus 20% DHA), 100 mg borage oil (20% GLA), and a mix of 15 mg vitamin E, and 25 mg of policosanols plus lipoic acid) twice daily in addition to either 60 mg/d isoflavones or placebo for 24 weeks reduced the number of moderate-to-severe hot flashes by 28.3 to 38.5% (p < 0.05) in 29 women (age 51 ± 5 years). The effects of PUFA supplementation on vasomotor symptoms were independent of isoflavone or placebo supplementation. The authors concluded, “PUFAs, particularly omega-3 fatty acids, could reduce hot flushes through their influence on neuronal membranes and/or the modulation of the neurotransmitter function and the serotoninergic system.”²⁹

Similarly, Lucas et al. investigated the effects of ethyl-EPA supplementation (1005 mg ethyl-EPA + 150 mg ethyl-DHA per day) on the frequency and intensity of hot flashes and quality of life scores in 120 emotionally distressed middle-aged women (40–55 years of age) with hot flashes using a double-blind, placebo-controlled, randomized clinical trial.¹ The average number of hot flashes was 2.8 per day at baseline. After 8 weeks, hot flash frequency decreased by a mean of 1.58 per day (95% CI, −2.18 to −0.98) corresponding to a significant 55% decrease in the ethyl-EPA group, compared with a mean decrease of 0.50 per day (95% CI, −1.20 to 0.20) or 25% decrease in the placebo group. There was a significant reduction in hot flash score (frequency × intensity) in the ethyl-EPA group compared with placebo; however, no change in hot flash intensity between groups. Menopause-Specific Quality of Life scores improved with both groups, however, was not significantly different between groups at end point.

In a preliminary open trial, Freeman et al. observed a reduction in the number of daily hot flashes and 24-hour hot flash scores (frequency and severity) with supplementation of 2 g/d omega-3 fatty acids (930 mg/d EPA + 750 mg/d DHA) for 8 weeks in 15 menopausal women.¹⁹ However, a follow-up study by the same research group using a 12-week randomized placebo controlled trial observed no effect of 1.8 g/day (1275 mg EPA + 300 mg DHA) of fish oil supplementation (n = 177) for the reduction in frequency or bother of vasomotor symptoms in peri- and postmenopausal women compared with an olive oil placebo (n = 178).³⁰ Therefore, due to the limited number of studies to date, more high-quality randomized controlled trials are needed to substantiate the efficacy of omega-3 long-chain PUFA for vasomotor symptom relief.

Hypertriglyceridemia and Cardiovascular Risk

Cardiovascular disease (CVD) is the leading cause of death in women worldwide, particularly postmenopausal women.³¹ Estrogen loss plays a major role in the increased risk of CVD.³² However, hormone replacement therapy has not been shown to be effective in reducing CVD risk in postmenopausal women and is associated with an increase risk of stroke and venous thromboembolic events; and questions remain as to the long-term effects in perimenopausal women.^33–35 Cardiovascular symptoms of menopause include increased heart rate, heart pounding or racing, irregular heartbeat, arrhythmias, atrial fibrillation, and blood lipid levels. Moreover, triglycerides (TG) are higher in postmenopausal women compared with premenopausal women, and increase blood TG levels occurs particularly in women receiving oral estrogen therapy, but not transdermal estrogen.^36,37

Omega-3 fatty acids can reduce TG levels by up to 45% in patients with severe hypertriglyceridemia (TGs ≥ 500 mg/dL).³⁶ Monitoring the lipid profile during the menopausal transition is critical and omega-3 EPA+DHA supplementation offer a well-tolerated option for hypertriglyceridemia. A randomized, double-blind, placebo-controlled crossover trial investigated the effects of 2.8 g/d of DHA for 4 weeks in postmenopausal women receiving and not receiving hormone replacement therapy.³⁸ In all women, regardless of hormone replacement therapy status, DHA supplementation resulted in a 20% decrease in TG, 8% increase in HDL-C, 28% decrease in the TG:HDL-C ratio, and a 7% decrease in heart rate as compared with placebo.

Mozaffarian and Wu reviewed the individual cardiovascular effects of EPA and DHA from human studies.³⁹ With respect to physiological risk factors, both EPA and DHA decreased TG levels, whereas EPA decreased HDL₃ cholesterol and DHA increased LDL particle size and HDL₂ cholesterol. In addition, DHA decreased blood pressure and heart rate, whereas EPA had minimal blood pressure effects and no clear effect on heart rate. For clinical endpoints, DHA reduced risk of atrial fibrillation and fatal CHD or sudden death, whereas EPA reduced risk of nonfatal coronary syndromes and congestive heart failure. The authors concluded, “the present evidence suggests that EPA and DHA have both shared and complementary benefits. Based on current evidence, increasing consumption of either would be advantageous compared to little or no consumption”.³⁹

The American Heart Association guidelines for the prevention of coronary heart disease in women recommends supplementation of omega-3 PUFAs to provide 850 to 1000 mg of EPA plus DHA daily, and higher doses of 2 to 4 g of EPA plus DHA daily for the treatment of women with high triglyceride levels.⁴⁰ Antiarrhythmic effects may be achieved with 500 to 1000 mg EPA+DHA per day.⁴¹

Joint Health

Over half of peri- and postmenopausal women experience some degree of joint pain and inflammation, fueled by a decline in estrogen levels and corresponding low serotonin levels.^2,42 Menopause arthritis is another term for joint pain during menopause; can affect the knees, hips, back, neck, shoulders and extremities; and may be associated with osteoporosis. Omega-3 EPA and DHA are effective in decreasing joint swelling and pain, tender joints, duration of morning stiffness, patients assessments of pain, and use of nonsteroidal anti-inflammatory drugs (NSAIDs).⁴³ Mechanistically, EPA and DHA provide immune-modulating and anti-inflammatory action (inhibit the production of prostaglandin [PG]E2 and leukotriene [LT]B4), promote the resolution of inflammation through production of resolvins and protectins, and reduce the production of inflammatory cytokines (i.e., IL-1β, IL-6, and TNF-α).⁴³

In a study of 125 patients with nonsurgical neck or back pain, supplementation of 1200 mg to 2400mg EPA+DHA for an average of 75 days resulted in a 59% reduction in NSAID and pain medicine use and a 60% improvement in joint pain, with 80% patient satisfaction and no significant side effects.⁴⁴ Research has substantiated the beneficial effects of EPA plus DHA on symptoms of arthritis. Results from meta-analysis suggest supplementing with >2.7 g/day of omega-3 EPA+DHA for >3 months, specifically in the reduction of NSAID consumption in rheumatoid arthritis patients, as well as improvements in tender joint count, swollen joints, morning stiffness, and physical function.^45,46 While the majority of clinical studies surround efficacy of EPA plus DHA for joint health in male and female patients, results may be extrapolated to the menopausal women.

Dry Eye Syndrome

Changes in hormonal balance during the menopausal transition are associated with a reduction in tear production and the onset of dry eye syndrome (DES). Patients with DES may experience a reduction of the quantity and quality of tears, an unstable tear film, ocular surface damage, and ocular symptoms such as irritation, dryness, fatigue, and variable visual disturbances.⁴⁷ DES effects approximately 7.8% of women 50 years or older in the US, compared with 4.7% of men.⁴⁷ Extended periods of dry eye is associated with inflammation of the ocular surface. Due to the role omega-3 PUFA EPA and DHA play in modifying the inflammatory process, much interest surrounds the use of omega-3 supplementation in the treatment of DES.

Currently, there are no clinical trials that investigate the effects of omega-3 PUFA supplementation on DES in peri- or postmenopausal women only. However, in a small randomized controlled trial, Kawakita et al. assigned either fish oil supplementation (1245 mg EPA plus 540 mg DHA daily) (n = 15) or placebo (n = 12) to patients with DES.⁴⁸ After 12 weeks, there was a significant improvement in eye pain subjective symptoms and measures of tear stability with fish oil supplementation compared with placebo. Results suggest fish oil supplementation accelerates recovery and effectively treats DES. While Wojtowicz et al. did not observe a change in tear stability, supplementation of omega-3 fatty acids (450 mg EPA, 300 mg DHA, and 100 mg flaxseed oil daily) for 90 days increased the average tear production and tear volume in 36 patients with DES compared with placebo.⁴⁹ In addition, 70% of patients supplementing with omega-3 fatty acids became asymptomatic at the end of the study, compared with 7% in the placebo group. A short-term study supplementing 180 mg EPA plus 120 mg DHA twice daily for 30 days observed a 71% improvement in tear evaporation, a 26% improvement in dry eye symptoms, and a 22% improvement in measures of tear secretion, results significantly better than the placebo group.⁵⁰ Therefore, EPA plus DHA supplementation shows much promise for effectiveness in DES in the menopausal transition.

Conclusion

The research reviewed supports the use of omega-3 PUFA, specifically EPA and DHA, as effective CAM for symptom relief in the menopausal transition. More specifically, women who are experiencing depression should supplement with higher levels of EPA to DHA and target a minimum daily dose of 1 g EPA for optimal efficacy. While daily supplementation of >3 g/d of EPA plus DHA are ideal for hypertriglyceridemia and joint health, more research is needed to substantiate the efficacy and optimal dose for hot flashes and dry eye syndrome in perimenopausal women. Inclusion of a high-quality fish oil supplement, providing targeted doses of EPA and DHA, in a patient’s treatment protocol may provide synergistic benefits and improve quality of life during the menopausal transition.

Notes

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Correspondence

Dr. Leah Gillingham

Chief Scientific Officer

Nutritional Fundamentals for Health Inc.

Direct: 613-876-7114

Head Office: 866-510-3123

leah@nfh.ca