The global burden of type 2 diabetes is rising and represents a major concern in healthcare worldwide. Global prevalence of type 2 diabetes is projected to increase from 6059 to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world. Consequently, urgent effective clinical preventive and supportive measures are warranted. In this context, pharmacological modulation of the endogenous cannabinoid system (ECS) is emerging as a promising therapeutic strategy in the pathogenesis of type 2 diabetes mellitus (T2DM) and its chronic complications. The Endogenous Cannabinoid System The endogenous cannabinoid system (ECS) comprises the endocannabinoids (ECs),
Endometriosis is a painful disorder characterized by the presence of endometrial (uterine) tissue in locations outside the uterus. This can include on or around the ovaries, on other structures within the pelvic cavity, and even in other locations around the body. Endometriomas, also described as hemorrhagic cysts, can be intrusive and adhesive to surrounding structures; and because they are made of endometrial tissue, they respond to cycling ovarian hormones.
There are many different stages and severities of endometriosis depending on infiltration of tissue, adhesion to surrounding organs and structures, the number of lesions and the symptoms experienced. As a result, endometriosis can present with severe pelvic pain at any time of the menstrual cycle, heavy menstrual flow, dyspareunia (painful intercourse) and dyschezia (pain during bowel movements).
We currently still haven’t completely determined how endometriosis develops. It is such a complex and multifactorial disorder that our original theories aren’t holding up on their own. For example, one of the earliest theories describes a “seeding” of endometrial tissue as a result of retrograde menstrual flow. However, the majority of women experience some amount of retrograde flow but only about 10% of these women will develop endometriosis.1 Therefore we know that other conditions must be present for these “seeds” of endometrial tissue to be able to adhere, proliferate, obtain a blood supply and respond to hormonal signals.
Immune function and Inflammation
One of the key characteristics of endometriosis is the evasion of the immune system. These cysts that form are allowed to proliferate without being tagged and removed by the immune system as an invader. Normally, the cells within shed menstrual endometrial tissue undergo apoptosis (cell death), however in women with endometriosis, more of these cells survive.2
It has been suggested that these cells escape immunological attack by secreting cytokines, chemical signalling molecules, to control certain aspects of immune system. Meanwhile, the local macrophages in endometriosis have reduced expression of the enzymes and receptors needed for scavenging debris and therefore fail to remove cells and debris from retrograde menstruation.3
Those with endometriosis have been found to have increased levels of inflammatory prostaglandins, cytokines and markers of oxidative stress. Estrogen dominance and a reduced response to progesterone both facilitate an environment where cytokines can continuously recruit aspects of the immune system and promote growth of endometriotic lesions.4
From there, lesion growth is assisted by the presence of vascular endothelial growth factor (VEGF), which creates a blood supply for the endometrial tissue.5
Diagnosis and conventional treatment options
Pelvic pain is cause for investigation, especially if the pain has become more intense or if it has been occurring more frequently, and not only during the menstrual cycle. Unfortunately, there is no single blood test for endometriosis. In some cases, estrogen levels may be abnormally high. Additionally, practitioners may test for a tumor marker called “CA-125.” Although associated with endometriosis, not having a positive CA-125 doesn’t mean you don’t have endometriosis, but having high levels of CA-125 likely means there are abnormal cells present.
An abdominal and transvaginal ultrasound is a non-invasive way of identifying the presence of lesions or abnormal tissue. However, a diagnosis of endometriosis cannot be confirmed without laparoscopic surgery to remove and properly identify endometrial lesions.
Primary interventions in endometriosis are aimed at pain management and lesion size regression (or elimination). Non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, are most commonly prescribed for pelvic pain relief. In many cases, NSAIDs can decrease pain, however; their recurring or chronic use is discouraged. In 2015, the FDA strengthened their warning on the use of NSAIDs due to the increased risk of heart attack and stroke within as little as the first weeks of use.6 To reduce the need for NSAIDs, oral contraceptives and hormonal therapies are often prescribed as an adjunct primary care.
Apart from immune dysfunction and inflammatory processes, endometriosis is heavily influenced by estrogen. Use of certain hormonal contraceptives has been shown to decrease pain and to limit the growth of endometriotic lesions.5 However, the use of these synthetic hormones cannot be used by women trying to conceive; as well, they may not be tolerated by all patients.
Surgical intervention is also an option, though it may affect future fertility outcomes. As mentioned above, investigatory laparoscopy is the gold-standard procedure for diagnosing endometriosis, and during this procedure, surgeons will remove lesions or reduce burden via excision and ablation. In patients with stage I or II endometriosis, this may improve their chances of pregnancy in the future2, however; there are no certainties and surgical intervention could also impede fertility by creating inflammation and/or tissue damage to the ovaries or surrounding structures.
Alternative Therapies and Adjuncts to Surgery
Because the pathophysiology of endometriosis is multifactorial, the approach to patient treatment should similarly address inflammation, immunomodulation, liver detoxification and promote healthy estrogen metabolism.
Antioxidant and Anti-inflammatory supplementation
Curcumin, known for its anti-inflammatory properties, has recently been shown to promote the regression of endometriotic lesions. One study found that curcumin could suppress the proliferation of endometriotic cells by reducing the level of estradiol and by inducing apoptosis.7 Curcumin has also been shown to down-regulate cell adhesion molecules and the expression of pro-inflammatory cytokines.8
Due to the nature of endometriosis and increased oxidative stress found in the peritoneal cavity, it’s been suggested that antioxidants could provide relief from endometriotic pelvic pain.9 One study showed that supplementing with antioxidants vitamin E and vitamin C for two months lowered the amount of inflammatory cytokines and reduced chronic pelvic pain in women with endometriosis.8 Among the patients on antioxidant therapy, 37% reported a decrease in dysmenorrhea and in pain intensity.8 Other antioxidants such as N-acetyl-cysteine (NAC) have also shown to reduce the size of endometriomas and prevent their growth.10
Resveratrol is a polyphenol found in grapes, wine, berries and nuts that has antioxidant, anti-inflammatory and anti-angiogenic properties.11 In vivo studies demonstrate that resveratrol can reduce the proliferation of endometriomas and induce cell death within lesions, while human clinical trials show that it may help decrease pain scores when combined with hormone therapy, more so than hormone therapy alone.11
The endocrine-immune relationship in endometriosis is complex, but both conventional and alternative treatments aim to control estrogen dominance and rebalance hormones in favour of progesterone.
One alternative to progestin (synthetic progesterone) therapy is the botanical Chaste Tree (Vitex agnus-castus), an estrogen antagonist and promoter of luteinizing hormone (LH) and progesterone. Because women with endometriosis tend to have a decrease in progesterone receptors, dosing is typically higher than for PMS or mastalgia. Chaste Tree may not be right for every patient with endometriosis, but may be helpful for women who prefer not to use synthetic hormones or those who do not wish to suppress ovulation.
Additionally, those with endometriosis need to be aware of the endocrine-disrupting effects of xenoestrogens and other synthetic chemicals found in plastics, make-up and body products, and in the foods we eat. Swapping out conventionally processed animal products for those from pasture-raised, grass-fed and/or organic sources can help decrease exposure to exogenous hormones and endocrine-disrupting chemicals.
Promoting healthy liver detoxification can have very positive effects in estrogen metabolism and in the elimination of toxins. Compounds such as Indole-3-Carbinol (I3C) and 3,3’-diindolymethane (DIM), both derived from vegetables in the Brassica family, promote anti-estrogenic and anti-androgenic effects.12 In addition to exerting anti-cancer and anti-tumor effects, I3C promotes Phase I and Phase II detoxification pathways in the liver, acting as a liver-protectant and estrogen modulator.12
Endometriosis is a multifactorial disorder with a complex pathophysiology. The dysregulation of immune cells and alterations in tissue function play major roles in the progression and presentation of the disorder. In addition to hormone regulation and estrogen balance, anti-inflammatories and antioxidants may be beneficial treatment options to decrease pelvic pain and promote regression of endometriotic lesions.
- Malvezzi H, Marengo EB, Podgaec S et al. (2020). Endometriosis: current challenges in modeling a multifactorial disease of unknown etiology. J Transl Med. 18: 311
- Burney RO and Giudice LC. (2015). Endocrinology: Adult and Paediatric. Chapter 130, Endometriosis., 2015; Elsevier Health Sciences.
- Podgaec S, Dias Junior JA, Chapron C, et al. (2010). Th1 and Th2 immune responses related to pelvic endometriosis. Rev. Assoc. Med. Bras. 56(1): 92-98
- Herington JL, Bruner-Tran KL, Lucas JA, et al. (2011). Immune interactions in endometriosis. Expert review of clinical immunology. 7(5):611-626
- Zito G, Luppi S, Giolo E, et al. (2014). Medical Treatments for Endometriosis-Associated Pelvic Pain. Biomed Res Int. Article ID 191967
- FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. (2015) U.S. Food and Drug Administration http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm Accessed July 26, 2015
- Zhang, Y., Cao, H., Yu, Z., Peng, HY., and Zhang CJ. “Curcumin inhibits endometriosis endometrial cells by reducing estradiol production” Iran J Reprod Med. 2013;11(5):415-22
- Kim KH, Lee EN, Park JK, et al. (2012). Curcumin attenuates TNF-alpha-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and pro inflammatory cytokines in human endometriotic stromal cells. Phytother Res. 26(7):1037-47
- Santanam N, Kavtaradze N, Murphy A., et al. (2013). Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. Transl Res. 161(3):189-95
- Halpern G, Schor E, Kopelman A. (2015). Nutritional Aspects Related to Endometriosis. Rev Assoc Med Bras. 61(6):519-23
- Dull A-M, Moga MA, Dimienescu OG, et al. (2019). Therapeutic approaches of resveratrol on endometriosis via anti-inflammatory and anti-angeogenic pathways. Molecules. 24(4): 667
- Acharva A, Das I, Singh S, et al. (2010). Chemopreventive properties of indol-3-carbinol, diindolymethane and other constituents of cardamom against carcinogenesis. Recent Pat Food Nutr Agirc. 2(2): 166-77