By Alex Ritson MSc, Head of Education

Research: Omega‐3 long chain polyunsaturated fatty acids as a potential treatment for reducing dysmenorrhoea pain: Systematic literature review and meta‐analysis by Snipe et al. (2023)

Context:

Quotes from female athletes:

• “In the worst of times, I’ll be doubled over and retching.”
• “Cramp, nausea, really bad… it would be like symptoms of an illness…”
• “When it’s real bad, I can’t, I won’t train, I’ll take the day off…” (Findlay et al., 2020)

Can you relate? These are athlete accounts of dysmenorrhea. Monthly, menstrual-related symptoms that result in cramping and pain in the pelvic region, which often spread to the lower back and thighs. Common symptoms are headache, nausea, vomiting, and diarrhoea (Proctor & Farquhar, 2006). Dysmenorrhea is a gynaecological condition experienced by up to 90% of menstruating women (Nagy & Khan, 2023). Athletes demonstrate a lower prevalence of dysmenorrhea which may be due to the pain-relieving effects of regular exercise (Armour et al., 2019; Taim et al., 2023). However, for those who do suffer, 89% report being affected in some manner (McNamara et al., 2022). Dysmenorrhea is influenced by various factors; however, a group of lipid compounds synthesised from the omega-6 fatty acid arachidonic acid play a key role (Ricciotti & FitzGerald, 2011). These are called prostaglandins. Specifically, prostaglandin F2α and prostaglandin E2, which constrict blood flow, stimulate uterine contractions, and signal immune cells to assist in endometrial repair (Barcikowska et al., 2020). While these processes are critical for healthy menstruation, when concentrations of these lipids become excessive, this increases the severity of uterine contractions and menstrual pain (Lundström & Green, 1978). Two-thirds of athletes report that their menstrual cycle negatively impacts their performance, and almost half of these athletes take analgesics to reduce menstrual-related symptoms (McNamara et al., 2022). Analgesics are pain-relieving drugs, with non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol being popular over-the-counter types used to reduce dysmenorrhea symptoms. They work by inhibiting the cyclooxygenase enzymes responsible for synthesising prostaglandins, with 67% of women experiencing symptom-relief with NSAID use (Marjoribanks et al., 2015; Proctor & Farquhar, 2006). Despite their efficacy for relieving menstrual pain, they can cause adverse effects, such as headache, fatigue, and gastrointestinal symptoms (Marjoribanks et al., 2015). Notably, in addition to their role in menstruation, prostaglandins help protect the stomach from, well, itself. These lipids stimulate the secretion of mucus from gastric epithelial cells that help form a protective barrier that shields the stomach lining from hydrochloric acid. Moreover, they stimulate the production of bicarbonate ions that help neutralise the harsh, acidic environment of the stomach (Tai & McAlindon, 2021). Therefore, chronic inhibition of prostaglandins through NSAID use increases the susceptibility to stomach injury. Considering these adverse effects, non-pharmacological alternatives have been explored to manage menstrual-related pain symptoms, including supplementation with omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA). Treatment with n-3 LCPUFA stems from the understanding that the omega-6 fatty acid arachidonic acid (a precursor to prostaglandin synthesis) competes for the same enzymes (delta-5-desaturate and delta-6-desaturase) as n-3 LCPUFA in its metabolism. Therefore, increasing the intake of n-3 LCPUFA, found predominantly in oily fish or via supplementation, relative to omega-6 fatty acids obtained from fats, oils, meats, poultry, cereals, and cereal-based products, should, in theory, reduce arachidonic acid metabolism, the production of prostaglandins and dysmenorrhea. Despite numerous studies investigating the validity of this hypothesis, a consensus on the efficacy n-3 LCPUFA supplementation on dysmenorrhea remains uncertain. Therefore, this research aimed to aggregate these studies into a systematic review and meta-analysis and evaluate statistically whether n-3 LCPUFA intake reduces dysmenorrhoea in women.

The study:

This was a prospectively registered systematic review and meta-analysis that assessed the effect of n-3 LCPUFA on prostaglandin levels and pain severity in women with primary or secondary dysmenorrhea. Studies included randomised controlled trials, crossover designs, and pre-to-post intervention studies.

A closer look: What does prospectively registered mean?

A prospectively registered study means the researchers make public the study objectives, methodology and endpoints of the research before conducting the study. This approach reduces the potential for duplication and, most importantly, ensures transparency in the research process. Specifically, it reduces the possibility of “p-hacking” or “data-dredging”. This is where researchers change direction with their analysis based on their collected data, searching their data to find a statistically meaningful finding. This practice increases the chance of producing a “false positive”. This is where the research findings occurred due to chance alone or other uncontrolled or unknown variables. This process is viewed as bad practice in research as it undermines the scientific process. Moreover, it muddies the water on the studied topic and in the context of medicine and nutrition could lead to harmful recommendations.

Essential knowledge: What is the difference between primary and secondary dysmenorrhoea?

Primary dysmenorrhea refers to painful menstrual cramps without a pelvic pathology. Symptoms include pain around the abdomen, back, and thighs and can develop into headache, nausea, vomiting and diarrhoea. Menstrual pain typically begins 24-48 hours before the menstrual flow starts and reduces several days later. Concentrations of prostaglandins are the main cause of primary dysmenorrhea. Primary dysmenorrhea symptoms typically improve with menstrual age. Secondary dysmenorrhea is pain caused by an underlying clinical issue with symptoms commonly occurring longer than primary dysmenorrhea. Common causes of secondary dysmenorrhea include endometriosis, fibroids, and adenomyosis, which increase in prevalence with age (Nagy & Khan, 2023). Endometriosis occurs when endometrial tissue grows outside of the uterus and around the ovaries and fallopian tubes. This additional tissue bleeds during menstruation, causing heavy menstrual bleeding and inflammation. Fibroids (also known as myomas) are non-cancerous muscular tumours that can develop in or on the uterus and disrupt endometrial shedding, which may result in increased inflammation and cramping. Adenomyosis is endometrial tissue growing in or on the uterine muscle. This causes the uterine walls to become enlarged and sensitive — increasing the painful effects of contraction. Each of these pathologies can increase prostaglandin levels, inflammation, and subsequent sensations of pain during menstruation.

Findings:

Following the end of the eight weeks of high-intensity training, blood measures from the placebo group demonstrated statistically significant falls in total leukocyte count (p <0.04) and monocytes (p <0.01). In contrast, changes in the spirulina group remained insignificant, apart from eosinophil, which increased. Moreover, those in the spirulina group demonstrated a higher average of both monocytes (p <0.05) and basophils (p <0.05) compared to the placebo group.

Results:

This systematic review contained 12 studies with a total of 881 participants (mean age: 22 years). Six studies recruited participants with primary dysmenorrhea, while the others didn’t specify. All studies used fish oil supplements, with the most common dose being 1,000 mg of fish oil containing 300 mg of n-3 LCPUFA. Supplements were typically taken for two to three months. Ten of the 12 studies showed a 22% to 66% reduction in menstrual-related pain from pre-to-post intervention with fish oil supplementation. In the meta-analysis, eight studies showed a large effect (d =1.020, 95% CI 1.526 to 0.514, p < 0.001) of n-3 LCPUFA for reducing pain severity in women with dysmenorrhea compared to the comparison group. Moreover, six studies that assessed analgesic use in participants showed that fish oil supplementation significantly reduced pain-relieving medication compared to the comparison group.

Essential knowledge: What does an effect size mean?

An effect size is a statistical measure of practical significance commonly used in meta-analyses to synthesise findings. It measures the difference between a variable in a specific study, which, in this instance, is the pain scores between participants who underwent the treatment condition (fish oil supplementation) and the comparison groups in the analysis. An effect size can be calculated in many ways, but a common measure is Cohen’s d. Cohen’s d measures the mean standard deviation of two groups (e.g., fish oil supplementation and the comparison group). Using Cohen’s d effect size criteria, effect sizes can be considered either small (0.2), medium (0.5), or large (0.8 or greater), meaning that the difference between the means was 0.2, 0.5, or 0.8 standard deviations. The greater the effect size, the greater the likelihood that the findings are of meaningful significance.

Relevance

To recap, supplementation with n-3 LCPUFA demonstrated a large effect (d=1.02) in reducing the severity of pain related to the menstrual cycle. Notably, no study reported prostaglandin concentrations; thus, the theory of a prostaglandin-reducing effect due to reduced arachidonic metabolism could not be determined. It’s also important to consider that the outcome variable reported was pain sensation — a highly subjective measure. This outcome can be compounded when different instruments are used and how and when they are used during an experiment. The authors note that the pain measuring methods performed by most studies included in the analysis lacked detail, which the reader should bear in mind when determining the validity of these findings. Other limitations include a lack of valid and reliable dietary assessment measures to determine dietary or supplemental intake of n-3 LCPUFA before the study and controlling for lifestyle factors that could influence pain ratings, such as exercise or smoking. Considering these limitations, women who experience dysmenorrhea may want to add 1,000 mg of fish oil (containing 300 mg of n-3 LCPUFA) to their supplement stack to reduce menstrual-related pain. For athletes, always ensure the supplement is third-party tested for banned substances.

Recommended reading:

Omega‐3 long chain polyunsaturated fatty acids as a potential treatment for reducing dysmenorrhoea pain: Systematic literature review and meta‐analysis by Snipe et al. (2023)

Complement this research with the We Do Science podcast episode:

The impact of Omega 3 fatty acids on training & performance with Dr Chris McGlory and the late Professor Kevin Tipton

References:

Armour, M., Ee, C. C., Naidoo, D., Ayati, Z., Chalmers, K. J., Steel, K. A., de Manincor, M. J., & Delshad, E. (2019). Exercise for dysmenorrhoea. The Cochrane Database of Systematic Reviews, 9(9), CD004142. https://doi.org/10.1002/14651858.CD004142.pub4

Barcikowska, Z., Rajkowska-Labon, E., Grzybowska, M. E., Hansdorfer-Korzon, R., & Zorena, K. (2020). Inflammatory Markers in Dysmenorrhea and Therapeutic Options. International Journal of Environmental Research and Public Health, 17(4), 1191. https://doi.org/10.3390/ijerph17041191

Findlay, R. J., Macrae, E. H. R., Whyte, I. Y., Easton, C., & Forrest (Née Whyte), L. J. (2020). How the menstrual cycle and menstruation affect sporting performance: Experiences and perceptions of elite female rugby players. British Journal of Sports Medicine, 54(18), 1108–1113. https://doi.org/10.1136/bjsports-2019-101486

Lundström, V., & Green, K. (1978). Endogenous levels of prostaglandin F2α and its main metabolites in plasma and endometrium of normal and dysmenorrheic women. American Journal of Obstetrics and Gynecology, 130(6), 640–646. https://doi.org/10.1016/0002-9378(78)90320-4

Marjoribanks, J., Ayeleke, R. O., Farquhar, C., & Proctor, M. (2015). Nonsteroidal anti‐inflammatory drugs for dysmenorrhoea. The Cochrane Database of Systematic Reviews, 2015(7), CD001751. https://doi.org/10.1002/14651858.CD001751.pub3

McNamara, A., Harris, R., & Minahan, C. (2022). ‘That time of the month’ … for the biggest event of your career! Perception of menstrual cycle on performance of Australian athletes training for the 2020 Olympic and Paralympic Games. BMJ Open Sport & Exercise Medicine, 8(2), e001300. https://doi.org/10.1136/bmjsem-2021-001300

Nagy, H., & Khan, M. A. (2023). Dysmenorrhea. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK560834/

Proctor, M., & Farquhar, C. (2006). Diagnosis and management of dysmenorrhoea. BMJ : British Medical Journal, 332(7550), 1134–1138.

Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(5), 986–1000. https://doi.org/10.1161/ATVBAHA.110.207449

Tai, F. W. D., & McAlindon, M. E. (2021). Non-steroidal anti-inflammatory drugs and the gastrointestinal tract. Clinical Medicine, 21(2), 131–134. https://doi.org/10.7861/clinmed.2021-0039

Taim, B. C., Ó Catháin, C., Renard, M., Elliott-Sale, K. J., Madigan, S., & Ní Chéilleachair, N. (2023). The Prevalence of Menstrual Cycle Disorders and Menstrual Cycle-Related Symptoms in Female Athletes: A Systematic Literature Review. Sports Medicine. https://doi.org/10.1007/s40279-023-01871-8