Cancer stories are powerful. They start off with some shock and disbelief, then the fighting for life comes and in some cases, the story has a fairly happy ending of remission. In a lot more cases, however, the story does not end well. These latter stories are full of reminiscing about life before illness and living well while dying from cancer. The incidence of cancer worldwide is on a continuous rise, with approximately 17 million new cancer cases in 2018 and an estimated 27.5 million new cancer cases each year, by 2040. Cancer research is trying to keep up with
Endometriosis and migraines share many similarities in epidemiology, pathogenesis, and the physical or psychiatric co-morbidities that can accompany them.1 In this article, we will explore the links between the two conditions and natural substances that could potentially alleviate them.
Endometriosis is a gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity and commonly associated with chronic pelvic pain and infertility.2 This tissue arises only in women of menstrual age, can grow or bleed cyclically, and may cause adhesions.3 Typical symptoms include pelvic pain, dysmenorrhea, and infertility.4 Overall, six to 10% of women of reproductive age suffer from endometriosis, it affects between 50 and 60% of women and teenage girls with pelvic pain, and up to 50% of women with infertility.5 While there is no definitive etiology of endometriosis, there are several hypotheses regarding how endometriotic lesions develop.2
Migraines are the most common cause of recurrent, severe headache. It is experienced at some point by over 20% of women and over 10% men.6 The propensity to suffer from migraines has a genetic basis, but individual attacks may be triggered by external or internal influences, and in some cases, for no apparent reason.6 Migraines typically present as recurrent episodic headaches and frequently have the following pain characteristics: a unilateral location, a pulsating quality, moderate-to-severe intensity, and typically made worse by any form of movement or even modest exertion.6 In addition, the attacks may be accompanied by other features such as dizziness, lack of appetite, nausea, photosensitivity, extreme sensitivity to noises, and smells, disturbances of bowel function, and so on.6
Migraines are a neurological disorder that also commonly occur in women of reproductive age.3 Research suggests that a co-morbid relationship exists between migraines and endometriosis.3 For example, the rate of migraines is similar between girls and boys during childhood but the prevalence in women of reproductive age is more than twice that of men in the same age group and the rate of migraine declines rapidly after age 65 years in both sexes.7 Menorrhagia, a frequent condition experienced by women with endometriosis, is also common in women with migraines, with 63% of migraine patients reporting a recent history of menorrhagia, compared to 37% of controls.8 Similarly, early menarche – a well-known risk factor for endometriosis – is also associated with an increased risk of migraines.9
Based on similar observations, the relationship between migraines and endometriosis in women of reproductive age (18 to 51 years) was explored in a large, population-based cohort study. The data from 20,220 endometriosis patients and 263,767 controls without endometriosis derived from the National Health Insurance Research Database of Taiwan containing outpatient and inpatient records from 2000 to 2007 were analysed by Yang and his team of researchers. Their results indicated that migraines are 1.70 times more common in women with endometriosis than in those without the disease even after adjusting for the possible effects of female hormone therapies on migraine attacks. In addition, migraines were more frequently reported in women experiencing pelvic pain, a common symptom of endometriosis, than in women without pelvic pain.3
Based on their data and previous studies, the researchers suggest that endometriosis and migraines may have a co-morbid relationship due to the association with female hormones. They evoke the facts that cycling estrogen is linked to both endometriosis and migraines. Oral contraceptives and menopausal hormone replacement therapy, can exacerbate migraines. Conversely, the decrease in estrogen accompanying menopause and the use of Danazol a well-known male hormone analogue often used in the management of endometriosis, can reduce migraine symptoms.
Why the Pain?
Increased pain sensitivity induced by one of the disorders may lead to a higher likelihood of developing the other.10 Different aspects of the pathophysiological pathways believed to underlie endometriosis and its apparent relationship with migraines have been proposed. For example, Berkley and her team suggest that mechanisms underlying these pains and sensitivity to estrogen involve the growth into the ectopic endometrial tissue of a nerve supply, which could have a varied and widespread influence on the activity of neurons throughout the central nervous system. In other words, the activation of sensory fibers similar to an endometriosis lesion within ectopic endometrial tissue could lead to neuronal hyperactivity throughout the central nervous system.11 According to the Taiwanese researchers, it is possible that the excessive number of activated and degranulating mast cells within the endometriosis lesions (or internal nerve structures) could induce the release of a host of proinflammatory and algesic mediators. These mediators may then sensitize primary afferent meningeal nociceptive neurons which cause hypersensitivity and hyperalgesia, and potentially trigger the migraine attacks.3
The good news is that the adoption of a healthy lifestyle and diet along with targeted supplements can go a long way when it comes to managing both debilitating conditions. Here are a few examples of scienced-based recommendations supported by clinical observation.
Magnesium supplements have been used extensively in migraine prophylaxis and treatment.12 The Nurses Health Study also found a statistically significant inverse relationship between magnesium intake and endometriosis.13 Since magnesium deficiency is so frequent and associated to both conditions, supplementation should be considered.
Tanacetum parthenium, commonly know as “feverfew” is a medicinal plant traditionally used as an anti-inflammatory agent to alleviate a wide range of conditions ranging from fevers, migraine headaches to menstrual and labor pain.14
Modern-day literature supports the use of Feverfew as an anti-inflammatory and antinociceptive agent. Tanacetum has been shown to inhibit the activity of prostaglandin (PG) synthetase, which stops arachidonic acid conversion into inflammatory PGs, mast cell degranulation, and subsequent release of histamine, serotonin, and other inflammatory cytokines, such as TNF-α, IL-1, NF-𝜅B, and IFN-g, as well as peritoneal cyclooxygenase.15
Palmitoylethanolamide (PEA) is a lesser-known substance although is has been studied for its several health benefits for the past eighty years. PEA is a long-chain fatty acid naturally produced by the body and found in foods such as egg yolk, soy, and sunflower oils. Considered a cannabimimetic compound, PEA has been receiving more attention lately due to its crucial role in the endocannabinoid system (ECS). The wonder molecule is produced locally by the cells, and it accumulates in tissues following an injury, physical stress, or pain. PEA exhibits direct and indirect mechanisms of action and it has been shown to enhance the action of other endocannabinoids through its “entourage effect”.16
The anti-inflammatory action of PEA is associated with its ability to inhibit the activation of mast cells that cause additional inflammation (such as the release of histamine). A meta-analysis involving 786 patients who received PEA and 512 controls published in Pain Physician in 2017 demonstrated that PEA was associated with significantly greater pain reduction compared to inactive control conditions. Artukoglu and his team concluded that: ‟PEA may be a useful treatment for pain and is generally well tolerated in research populations.”16 A small study involving patients suffering of Migraines with Aura (MA) who received 1,200 mg of micronized PEA per day in combination with NSAIDs for up to 90 days showed that it had good efficacy and safety. The authors concluded that PEA can be considered as a therapeutic tool in pain migraine management.17 Di Paola and her team reported that co-micronized PEA and polydatin, a natural precursor of resveratrol. (PEA/PLD) decreased endometriotic lesions due to its antiangiogenic effect. This combination also decreased the levels of nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression (MMP-9), and lymphocyte accumulation.18
Other interesting supplements to be considered would include a bioactive, B Complex vitamins, a curcuma supplement providing free-curcumin, omega 3 fatty acids and systemic enzymes, to name a few. Maintaining a healthy gut and microbiome environment should also be a priority in managing migraines and endometriosis.
Achieving optimal hormonal balance throughout our reproductive years can be challenging but it can alleviate and prevent several health conditions, including migraines and endometriosis. Although genetics are often blamed for such conditions, we now know that genes are not our destiny! We can modulate those genes through a healthy lifestyle, a balanced diet, and targeted high-quality nutritional supplements. Proper genomic and functional testing may be useful in designing an individualized and efficient recommendations.
- Sepulcri Rde P, do Amaral VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol. 2009;142:53–56. https://pubmed.ncbi.nlm.nih.gov/19010584/
- Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, Diagnosis and Clinical Management. Curr Obstet Gynecol Rep. 2017;6(1):34-41. doi:10.1007/s13669-017-0187-1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737931/
- Yang MH, Wang PH, Wang SJ, Sun WZ, Oyang YJ, Fuh JL. Women with endometriosis are more likely to suffer from migraines: a population-based study. PLoS One. 2012;7(3):e33941. doi:10.1371/journal.pone.0033941 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307779/
- Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698–2704. https://pubmed.ncbi.nlm.nih.gov/15980014/
- Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362:2389–2398. https://pubmed.ncbi.nlm.nih.gov/20573927/
- Weatherall MW. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis. 2015;6(3):115-123. doi:10.1177/2040622315579627
- Victor TW, Hu X, Campbell JC, et al. Migraine prevalence by age and sex in the United States: a life-span study. Cephalalgia. 2010;30:1065-1072.
- Tietjen GE, Conway A, Utley C, Gunning WT, Herial NA. Migraine is associated with menorrhagia and endometriosis. Headache. 2006;46:422–428. https://pubmed.ncbi.nlm.nih.gov/16618258/
- Aegidius KL, Zwart JA, Hagen K, Dyb G, Holmen TL, et al. Increased headache prevalence in female adolescents and adult women with early menarche. The Head-HUNT Studies. Eur J Neurol. 2011;18:321–328. https://pubmed.ncbi.nlm.nih.gov/20636369/
- Karamustafaoglu Balci B, Kabakci Z, Guzey DY, Avci B, Guler M, Attar E. Association between endometriosis, headache, and migraine. Journal of Endometriosis and Pelvic Pain Disorders. 2019;11(1):19-24. doi:10.1177/2284026518818975
- Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308:1587–1589. https://pubmed.ncbi.nlm.nih.gov/15947176/ https://pubmed.ncbi.nlm.nih.gov/15947176/
- Dolati S, Rikhtegar R, Mehdizadeh A, Yousefi M. The Role of Magnesium in Pathophysiology and Migraine Treatment. Biol Trace Elem Res. 2020 Aug;196(2):375-383. doi: 10.1007/s12011-019-01931-z. Epub 2019 Nov 5. PMID: 31691193. https://pubmed.ncbi.nlm.nih.gov/31691193/
- Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA. Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013;177(5):420-430. doi:10.1093/aje/kws247
- Pareek A, Suthar M, Rathore GS, Bansal V. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 2011;5(9):103-110. doi:10.4103/0973-7847.79105 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210009/
- Ilhan M, Gürağaç Dereli FT, Akkol EK. Novel Drug Targets with Traditional Herbal Medicines for Overcoming Endometriosis. Curr Drug Deliv. 2019;16(5):386-399. doi:10.2174/1567201816666181227112421
- Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH. Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain Physician. 2017;20(5):353-362. https://pubmed.ncbi.nlm.nih.gov/28727699/
- Chirchiglia D, Cione E, Caroleo MC, et al. Effects of Add-On Ultramicronized N-Palmitol Ethanol Amide in Patients Suffering of Migraine With Aura: A Pilot Study. Front Neurol. 2018;9:674. Published 2018 Aug 17. doi:10.3389/fneur.2018.00674
- Di Paola R., Fusco R., Gugliandolo E., Crupi R., Evangelista M., Granese R., Cuzzocrea S. Co-micronized palmitoylethano-lamide/polydatin treatment causes endometriotic lesion regression in a rodent model of surgically induced endometriosis. Front. Pharmacol. 2016;7:382. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063853/