CRx MAGAZINE

Fall 2019

Easing Endometriosis

Research points to cannabis as an evolving treatment option for this common and debilitating condition.

Endometriosis is an inflammatory condition affecting 6% to 10% of reproductive-age women—almost 180 million worldwide. Its prevalence is 38% in infertile women and up to 87% in those suffering from chronic pelvic pain. There doesn’t appear to be a racial predisposition, though first-degree relatives have a seven- to 10-fold increased risk of endometriosis.1 The estimated cost to the United States is more than $20 billion a year.2 It’s a devastating condition resulting in pain, suffering, infertility, time off from work and school, and a host of emotional and psychologic tolls.3 For clinicians, it’s exceedingly frustrating to treat patients, as there is no cure for the disease and most of the treatment modalities offer modest, temporary relief at best.

The etiology of endometriosis may be multifactorial, though the most accepted cause is retrograde menstruation, which results in the implantation of endometrial glands and stroma on the peritoneum in the pelvis and abdomen. Hematogenous or lymphatic spread, stem cells from bone marrow, and coelomic metaplasia may help explain the presence of distant disease in lungs, extremities, and other locations.1 There are many theories about the etiology of endometriosis, from genetic and epigenetic factors to environmental pollution—eg, endocrine-disrupting chemicals such as diethylstilbestrol and dioxin.4-6

Why endometriosis flourishes in some patients and not others is not understood, but it could be due to immune or genetic susceptibility resulting in altered expression of endometrial genes and of hormonal response.7-9 Those suffering from endometriosis have increased prostaglandins due to cyclooxygenase-2 (COX-2) activity and increased estrogens due to aromatase activity, and this has led to medications targeting these pathways.10

The endometriotic lesions themselves lead to inflammation and pain through the action of cytokines and activated macrophages, notably tumor necrosis factor-alpha (TNF-alpha) and interleukin 1, 6, and 8.11 These cytokines induce prostaglandins, which increase pain. Nerve growth factor is highly expressed as well.

The association with infertility is indisputable, but the mechanism is unclear. The increased inflammatory state might result in a hostile environment leading to the destruction of sperm, altered egg transport, or, in severe cases where there is anatomic disruption, tubal occlusion.1

Risk factors for endometriosis include the onset of menarche prior to age 11, cycles of fewer than 27 days, and heavy, prolonged cycles. Higher parity, increased lactation duration, and regular exercise of more than four hours a week decrease risk.12 Diagnosis can only be made through laparoscopic examination and biopsy. Histology demonstrates endometrial stroma and glands with the associated inflammation in the tissues.

Treatment
Currently accepted treatment options targeting both infertility and pain include medical, surgical, and alternative therapies and assisted reproductive technologies.13 Combination oral contraception pills and gonadotropin-releasing hormone (GnRH) agonists are ineffective treatments for infertility, though excision of endometriomas has become standard practice, as this increases pregnancy rates significantly (60.9% following excision vs 23.4% following drainage and ablation).1

In the treatment of pain, nonsteroidal anti-inflammatory drugs have some utility, though they have not been shown to work specifically on endometriosis pain.14,15 Depot medroxyprogesterone acetate can be effective for pain, though the related osteoporosis is a significant concern.16

Intuitively, avoiding menstruation is a favored treatment option, and extended-cycle oral contraception pills and progestin-secreting intrauterine devices have been shown to significantly decrease pain.17,18

Danazol, an androgen, while effective, has bothersome side effects such as hirsutism, acne, and myalgias and has largely been replaced by GnRH agonists; these have significant side effects as well, such as vaginal dryness, hot flushes, and osteopenia. All of these treatment options are limited, as they work only while they are actively being used. Depot medroxyprogesterone acetate can be an effective treatment, but amenorrhea can linger up to 18 months after discontinuation, which can be a concern for those wanting to conceive. There are many other medications that have been studied but have limitations either in efficacy or due to unwanted side effects.1

A Need for New Approaches
Clearly, there’s a need to develop new treatment modalities that don’t induce anovulation or debilitating side effects. Inhibition of inflammation using TNF-alpha and COX-2 inhibitors is of particular interest, as COX-2 expression is higher in ectopic endometrial cells.10,19 A study by Russo postulated a clinical endocannabinoid deficiency that may underlie the pathophysiology of certain disease states, especially those associated by hyperalgia, and research into the inner workings of the endocannabinoid system is ongoing.20

Cannabis research has exploded of late due to the increased prevalence of medical and legal programs in the United States as well as in countries including Uruguay, Israel, and Canada, where increased numbers of studies are now available. Obviously, our knowledge base has been quite limited due to the federal illegal status that remains in the United States, though cannabis has been used historically, especially in women’s health and particularly in the treatment of chronic pelvic pain, reproduction, dysmenorrhea, and infertility.21

The Endocannabinoid System
Many practicing physicians did not have the benefit of being exposed in medical school to information about the endocannabinoid system that most creatures on the planet share, as it’s been a recent and ongoing discovery. While THC was discovered in 1964 by Raphael Mechoulam, PhD, it wasn’t until much later that our own endocannabinoids and receptors were defined—a process that is ongoing. Our endocannabinoid system regulates pain, immune response, mood, metabolism, reproduction, energy balance, appetite, memory, movement, thermogenesis, and the cardiovascular system.22 The uterus, specifically, is densely wired with CB1 and CB2 receptors.21,22

Endocannabinoids are lipid-signaling molecules that are quickly produced on demand in the cell membrane from phospholipid precursors. The most prominent include N-arachidonoylethanolamine (also known as anandamide [AEA]), and 2-arachidonoylglycerol (2-AG), which bind to CB1 and CB2 receptors. AEA levels are highest at ovulation, and AEA is in the highest concentration in uterine tissue compared with other reproductive structures.22 THC binds preferentially to CB1 receptors, which are most densely present in the central nervous system but also reside in the uterus. CB2 receptors reside in the peripheral tissues, immune system, and organs, including the uterus.23

Cannabis
Humans have known about cannabis and its healing potential for millennia, and records of its use have been unearthed in Asia dating back more than 10,000 years. It’s not clear when cannabis evolved, but it could have been as long as 50 million years ago. Some reports have estimated it originated in central Asia.24 The rich supply of cannabinoids residing in the plant may have evolved as a defense to the ultraviolet radiation due to high altitudes or possibly as a defense against being consumed by the local fauna. Many cannabinoids are, in fact, excellent insecticides.25 In any case, humans quickly embraced the plant and spread it throughout the globe along the trade routes used for tea and spices.

Cannabis was a part of the US Pharmacopeia in the 1800s and into the early 1900s. It usually was prescribed as a tincture, and special attention was given to its use in women’s health, for which it historically has been quite effective.21 Cannabis therapy fell out of favor when aspirin and morphine tablets were developed and was removed from the market when the United States began its war on drugs in the mid to late 1900s.26

Cannabis is made up of hundreds of compounds including the major phytocannabinoids THC and CBD, plus terpenes, terpenoids, and flavonoids that all play a complex role in modulating their effects on the body through the entourage effect—whereby the whole of the plant and its compounds are greater than the sum of its parts.25 This makes cannabis medicine particularly difficult, as it’s almost impossible to ferret out which compound or combination of compounds produces the desired effect. That said, there’s been progress to that end.

To name a few, Dronabinol, a synthetic form of THC, has been commercially available to treat nausea and vomiting and excessive weight loss in AIDS patients since the 1980s, and Epidiolex, synthetic CBD, was recently released for the treatment of severe seizure disorders. While these medications have some benefit, they’re said to give a “one note” effect due to the lack of entourage effect. Anecdotal reports from those who use cannabis for symptom relief often indicate a greater improvement in symptoms with a decrease in annoying side effects often associated with the synthetic cannabinoids.

Cannabis and Endometriosis
While there are numerous anecdotal reports of cannabis easing women’s pelvic pain, dysmenorrhea, and dyspareunia, it’s important to elucidate the science behind this and try to delineate it, which will make the formation of new treatment modalities relevant and necessary. With the discovery of CB1 and CB2 receptors, the focus now is on developing receptor-specific agonists and antagonists as potential therapies.27

The endocannabinoid system and its components have been shown to affect inflammation, cellular proliferation, and cellular vitality, which are implicated in the establishment and stimulation of endometriosis.28,29 There are many processes involved in the chronic inflammatory state of endometriosis and many potential pathways through which the cannabinoid system might be manipulated to address them.

Cannabinoids are excellent anti-inflammatories and are quite effective at reducing pain. They work in four ways: induction of apoptosis of T cells, B cells, and macrophages; inhibition of cell proliferation; suppression of cytokine production (including TNF-alpha); and induction of T-regulatory cells. CBD and THC are both effective in regulating the immune system.30,31 Because CB2 receptors are primarily found on immune cells, it might be possible to target inflammatory disorders such as endometriosis without psychotropic side effects.13

A comprehensive review summarized the following: Cannabinoids can regulate apoptosis by modulating death-signaling factors that are present in altered levels in endometriosis.32 Cellular migration is of concern in endometriosis as it is in cancer. Studies have demonstrated that cannabinoids regulate matrix metalloproteinase (MMP) levels in cancer cells, and, given the high levels of MMPs in ectopic endometrium, it can be postulated that this could be a valuable area of future study. MMPs are key players in the progression of cancer and have been implicated in initiation, progression, and metastasis.33 CB1 receptor activation modulates cellular proliferation, which is altered in endometriosis. Cannabinoids can decrease the vascular supply surrounding tumors, which would be of great interest.34 Cannabinoids work well as anti-inflammatories, as has been demonstrated. Finally, cannabinoids have been proven efficacious in the treatment of chronic inflammatory pain.35

Pain is a complex problem in endometriosis. Nociceptive, inflammatory, and neuropathic pain are all involved. Decreasing inflammation and disrupting pain pathways when endometriosis first presents in adolescents may decrease long-term pain syndromes.13,36 Recent studies in rats have demonstrated that CB1 receptors are expressed in ectopic endometrial tissue. In fact, endometriotic cysts have higher concentrations of these receptors than exist in uterine endometrium. It appears that ectopic endometrium recruits its own sensory and sympathetic nerve supply, which may involve the endocannabinoid system as it relates to neural pathways. Furthermore, CB1 and CB2 receptor antagonists increased endometriosis pain, but only CB1 agonists and not CB2 agonists decreased endometriosis pain. CB1 receptors have also been identified in rat blastocysts, implicating the endocannabinoid system in normal fetal implantation and failure of such.35

A limitation in cannabinoid signaling may play a role in the increased proliferative behavior of endometriotic lesions. Another study looked at blocking CB1 receptors and found that it may alleviate nerve formation involved in endometriosis-associated pain.37 Furthermore, endocannabinoids induce apoptosis, indicating that CB1 and CB2 receptor antagonists could be considered therapies for endometriosis and adenomyosis.38 Cannabinoid agonists have also been found useful in preventing cell proliferation and fibrosis in deep infiltrating endometriosis in vitro.39

Emerging Research
Ongoing studies include those by Strainprint, a Toronto-based provider of cannabis data and analytics, partnering with Lumir Lab and Gynica, which has permission from the Israeli Ministry of Health to conduct research on cannabis and gynecologic disorders. The studies are ongoing in Israel and Canada and hope to recruit as many as 1,000 patients in each country. They aim to identify which cannabinoids, terpenes, and flavonoids in relative combination provide the most effective relief.40

Endometriosis is a devastating condition involving hormonal and immunological aberrations. Its impact on women, families, and society is significant. Emerging research is looking into cannabis as a therapy for endometriosis and many other inflammatory conditions, worth consideration given the unique pathway in which cannabinoids work within the body.30,31 The fact that CBD has been implicated in modulating cellular migration in endometriosis as well as other cellular processes supports the need to maintain cannabis chemovars that are rich in this cannabinoid as well as the need to study the impact of the terpenes and terpenoids on disease states. The recreational and black market has pushed higher and higher THC levels, but the real magic of the plant may be the components originally found hundreds if not thousands of years ago, including CBD and rich terpene levels. Targeting cannabinoid receptors is an exciting new treatment modality that bears future attention and investigation.

— Leslie Apgar, MD, FACOG, is a board-certified OB/GYN who specialized in minimally invasive surgery until she retired from her private practice in 2017. She opened a medical cannabis dispensary in Maryland along with her best friend, and they developed a cannabis line for women in 2018 (www.blissiva.com and www.greenhousewellness.com).

IN PRACTICE

In my practice at the dispensary, I often treat women with chronic inflammatory conditions including endometriosis. Once I establish their previous experience with cannabis, I start them on tinctures three times a day. I like the Healer Balance tincture, which is equal parts THC, cannabidiolic acid, and CBD. I then add chewable tablets of 5 mg CBD plus 5 mg THC one to three times a day, adding an additional 5 mg of THC to address the patient’s pain if needed. Last, I advise patients to use vape pens for immediate relief during the day or to help them fall asleep at night. Depending on their pain level, these vary from 1:1 to 3:1 THC to CBD.

— LA

References

1. Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010;116(1):223-236.

2. Rogers PA, D’Hooghe TM, Fazleabas A, et al. Priorities for endometrial research: recommendations from an international consensus workshop. Reprod Sci. 2009;16(4):335-346.

3. Johnson NP, Hummelshoj L; World Endometriosis Society Montpelier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

4. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Michels KB, Hunter DJ. In utero exposures and the incidence of endometriosis. Fertil Steril. 2004;82(6):1501-1508.

5. Cummings AM, Hedge JM, Birnbaum LS. Effect of prenatal exposure to TCDD on the promotion of endometriotic lesion growth by TCDD in adult female rats and mice. Toxicol Sci. 1999;52(1):45-49.

6. Crain DA, Janssen SJ, Edwards TM, et al. Female reproductive disruption: the roles of endocrine disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911-940.

7. Garrido N, Navarro J, García-Velasco J, Remoh J, Pellice A, Simón C. The endometrium versus embryonic quality in endometriosis-related infertility. Hum Reprod Update. 2002;8(1):95-103.

8. Meresman GF, Vighi S, Buquet RA, Contreras-Ortiz O, Tesone M, Rumi LS. Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis. Fertil Steril. 2000;74(4):760-766.

9. Guo SW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587-607.

10. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268-279.

11. Bedaiwy MA, Falcone T, Sharma RK, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod. 2002;17(2):426-431.

12. Shafrir AL, Farland LV, Shah DK, et al. Risk for and consequences of endometriosis: a critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. 2018;51:1-15.

13. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-1349.

14. Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2009;(2):CD004753.

15. Matsuzaki S, Canis M, Pouly JL, Botchorishvili R, Déchelotte PJ, Mage G. Both GnRH agonists and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis. Hum Reprod. 2007;22(1):124-128.

16. Kaunitz AM, Arias R, McClung M. Bone density recovery after depot medroxyprogesterone acetate injectable contraception use. Contraception. 2008;77(2):67-76.

17. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 2003;80(3):560-563.

18. Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra-uterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod. 2005;20(3):789-793.

19. Clemenza S, Sorbi F, Noci I, et al. From pathogenesis to clinical practice: emerging medical treatments for endometriosis. Best Pract Res Clin Obstet Gynaecol. 2018;51:92-101.

20. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2004;25(1-2):31-39.

21. Russo E. Cannabis treatments in obstetrics and gynecology: a historical review. J Cannabis Ther. 2002;2(3-4):5-34.

22. Di Blasio AM, Vignali M, Gentilini D. The endocannabinoid pathway and the female reproductive organs. J Mol Endocrinol. 2013;50(1):R1-R9.

23. Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202.

24. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4(8):1614-1648.

25. Russo E. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.

26. Frye PC, Smitherman D. The Medical Marijuana Guide: Cannabis and Your Health. Lanham, MD: Rowman & Littlefield; 2018.

27. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47(Suppl 1):345-358.

28. Bouaziz J, Bar On A, Seidman DS, Soriano D. The clinical significance of endocannabinoids in endometriosis pain management. Cannabis Cannabinoid Res. 2017;2(1):72-80.

29. Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol. 2009;156(3):397-411.

30. Elikkottil J, Gupta P, Gupta K. The analgesic potential of cannabinoids. J Opioid Manag. 2009;5(6):341-357.

31. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8(6)403-421.

32. Sanchez AM, Vigano P, Mugione A, Panina-Bordignon P, Candiani M. The molecular connections between the cannabinoid system and endometriosis. Mol Hum Reprod. 2012;18(12):563-571.

33. Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278(1):16-27.

34. Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci U S A. 2000;97(20):10972-10977.

35. Dmitrieva N, Nagabukuro H, Resuehr D, et al. Endocannabinoid involvement in endometriosis. Pain. 2010;151(3):703-710.

36. Medina MG, Lebovic DI. Endometriosis-associated nerve fibers and pain. Acto Obstet Gynecol Scand. 2009;88(9):968-975.

37. Han H, Liang X, Wang J, et al. Cannabinoid receptor 1 contributes to sprouted innervation in endometrial ectopic growth through mitogen-activated protein kinase activation. Brain Res. 2017;1663:132-140.

38. Bilgic E, Guzel E, Kose S, et al. Endocannabinoids modulate apoptosis in endometriosis and adenomyosis. Acta Histochem. 2017;119(5):523-532.

39. Leconte M, Nicco C, Ngô C, et al. Antiproliferative effects of cannabinoid agonists on deep infiltrating endometriosis. Am J Pathol. 2010;177(6):2963-2970.

40. Solomon S. Israeli researchers probe how cannabis can treat endometriosis. The Times of Israel. April 24, 2019. http://timesofisrael.com/israeli-researchers-probe-how-cannabis-can-treat-endometriosis/

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