Endometriosis is a chronic gynecological condition causing pelvic pain, menstrual irregularities, infertility and misery affecting 6-10% of women in the United States.(1)(7) The worldwide incidence of endometriosis is estimated to be between 0.1 and 0.3%, or about 150 to 200 million women.(17) Conventional Medical treatment is largely ineffective. Surgical treatment with laparoscopy is used as a last resort to restore fertility and relieve pain.(2) In this article we will discuss natural treatments for endometriosis.
Above header image courtesy of Dr Seckin, Laparoscopic surgery for endometriosis.
What is Endometriosis ?
In this condition, the cells from the lining of the uterus called the endometrium are found at distant locations outside the uterus, with tissue deposits scattered throughout the peritoneal cavity. The mechanism, confirmed in animal experiments, is thought to be retrograde passage of menstrual endometrium through the fallopian tubes. These cells then seed the surface of the ovaries as well as the entire peritoneal cavity.(3)
“The primary theory of the pathogenesis of endometriosis…(is) the retrograde “regurgitation” of endometrial cells passing through the oviducts into the peritoneal cavity and proliferates in ectopic sites”. Quote from Dr. Ceccaroni (4)
Coexisting abnormalities of host immunity are also found. required to allow for abnormal implantation of the endometrial tissue. (1)
When doctors visualize the ovaries or the peritoneal lining with the laparoscope instrument, they may find implanted small dark nodules of endometrial tissue (see image below) . Microscopic examination of the endometrial implants shows induction of blood and nerve supply to the implants,
Above image: Shows Laparoscopic view of endometrial implants on peritoneal cavity ( Dark spots denoted by red arrows) courtesy of Dr. Yahya Kamal
Features Shared with Cancer
Although endometriosis is benign disease, it shares many of the features of cancer cells, and can be viewed as a neoplastic process.(5) There is extensive clinical, pathologic, and molecular evidence suggesting that endometriosis is a neoplastic process with a potential for malignant transformation.(5) Endometriosis may show up on cancer imaging with PET scanning giving a false positive scan.(6)
Resveratrol and ECGC, Fish Oil and Melatonin
If this is true, that endometriosis is a neoplastic process, then one might expect endometriosis to regress in response to natural substances that have anti-cancer activity, such as Resveratrol, ECGC (green tea), Fish oil and Melatonin. These have been studied in animal models.
Resveratrol is a natural substance obtained from red wine which has anti-proliferative and anti-inflammatory properties.(11) ECGC is an extract from green tea. A 2013 study by Dr Riccifound both Resveratrol and ECGC had a potent inhibitory effect on the development of endomeriosis in a mouse model. (7)
A 2011 study by Dr. Brune-Tran showed that Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro. (8) In this study, nude mice were implanted with human endometriosis cells.(8) The authors found that Resveratrol decreased the number of endometrial implants by 60% and decreased total volume of implants by 80%.(8) This is quite an impressive result for a natural occurring supplement.
Omega -3 Fatty acids in fish oil are known to have anti-inflammatory properties. A 2014 study by Dr. Jennifer L. Herington using an experimental mouse model of endometriosis, showed that in mice with a 10% supplemented fish oil diet, adhesion score and disease burden were significantly reduced. (9) The authors concluded,”an antiinflammatory diet that includes fish oil supplementation may be a beneficial adjuvant to reduce development of adhesions in women undergoing surgical treatment of endometriosis.”(9)
Melatonin has anti-cancer and anti-inflammatory properties and was studied by Dr. Guney in 2008 in a mouse model of endometriosis. (10) The authors found that Melatonin causes regression and atrophy of the endometriotic lesions in experimental mice.(10)
Adenomyosis is similar to endometriosis with similar ectopic implantation of endometrial tissue, in this case, the ectopic tissue resides within the uterus itself, in the muscular layer of the uterine wall where endometrial glandular tissue should not be found. Induction of adenomyosis in mice results in progressive hyperalgesia (increased sensitivity to pain), uterine hyperactivity, and elevated plasma corticosterone levels (indicating stress).(13-14)
ECGC, an extract of green tea has been found to possess anti-cancer activity (12). Two publications deal with ECGC as a beneficial natural treatment for adenomyosis.(13-14) In a 2013 study, Dr Chen found that EGCG suppresses myometrial infiltration, improves generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels in experimental mice induced with adenomyosis. (13-14)
Cyclic Natural Progesterone for Endometriosis
Another natural treatment which we have used successfully over the years is cyclic progesterone, 20-40 mg twice a day applied as a topical cream for days 8-26 of the menstrual cycle. This was pioneered by John R Lee MD and described in his book, Natural Progesterone: The Multiple Roles of a Remarkable Hormone
Patients have reported good results with this regimen with relief of pain and other symptoms of endometriosis.
Dr Jeri Lynn Prior protocol with oral Prometium 300 mg BID.
Dr. Lam protocol for endometriosis – 20 mg topical progesterone BID days 8-26..
Women in Balance on Progesterone cream for endometriosis.
Medicinal Cannabis Beneficial for Endometriosis
If it is true that endometriosis is a benign disease that responds to natural substances with anti-cancer activity, then one would expect cannabis sativa extract to have beneficial effects. This is exactly what was found in multiple studies.(15-19) An additional benefit, reduction in pain was also reported. (15-19)
Pain from Endometriosis and the EndoCannabinoid System
Dr Dmitrieva studied the Endocannabinoid involvement in endometriosis and reported his findings in the journal Pain in 2010. He noted that previous endometriosis studies in mouse models and in women showed : “sensory and sympathetic nerve fibers sprout branches to innervate” the endometriosis implants.” In the past, medicinal cannabis was commonly used for control of endometriosis-associated pain. Dr. Dmitrieva theorized that the endocannabinoid system is involved in both endometriosis and its associated pain. Using a mouse model of endometriosis, Dr Dmitrieva found that CB1 cannabinoid receptors are expressed on the sensory and sympathetic nerves to the endometriosis implants.(15)
Progesterone and the Endometrium
Dioxin Disrupts Cannabinoid Signalling in the ENdometrium
In the Oct 2012 Fertility and Sterility, Dr. Kevin G. Osteen, proposed that exposure to environmental endocrine disruptor chemicals, such as dioxin, may trigger changes that promote progesterone-resistant endometriosis. He did a molecular study of the CB1 receptor Messenger RNA in endometriosis. He analysed Cannabinoid Receptor Messenger RNA (CB1-R mRNA) in human endometrial tissues before and after exposure to Dioxin, (TCDD) or a progesterone receptor antagonist drug, Onapristone.(16)
Dr. Osteen found that progesterone exposure in vivo during the secretory phase (days 12-26 of cycle) was associated with upregulation of endocannabinoid receptors in normal women. Dr. Osteen found increased genetic expression of endocannabinoid receptor (CB1-R) messenger RNA in endometrial tissue samples harvested from healthy normal women during days 12-26 of the menstrual cycle. However, there was no upregulation of gene expression in women with endometriosis. They found very little, or reduced expression of CB1-R gene expression in similar endometrial tissue samples taken from women with endometriosis.
The in vitro studies revealed that acute Dioxin exposure to normal endometrial cells produced this same abnormality, resulting in a failure of progesterone to up-regulate endocannabinoid receptor expression. The same results were obtained with a Progesterone antagonist drug.
The authors concluded that loss of normal progesterone responsiveness, ie. progesterone resistance, is a striking feature of endometriosis. In addition, the progesterone-mediated endometrial endocannabinoid receptor system was profoundly dysfunctional in women with endometriosis. Exposure to the endocrine disrupting chemical, Dioxin, replicated these abnormalities (16)
Left Image: Upper Frame: Green arrow denotes normal increase in endocannabinoid receptor gene expression in normal patients. Red arrow denotes endometriosis patients with low gene expression during early phase and no increase in secretory phase. Lower frame: Histology slide of endometrial samples showing normal brown staining of receptor proteins (green ellipse). And absent staining in tissues from endometriosis patient (red ellipse Images courtesy of authors . and the NIH.(16) Link to Image.
In 2012 in the journal Molecular Human Reproduction, Dr Sanchez from Milan Italy, published his review of the medical literature (metanalysis) on the molecular connections between the cannabinoid system and endometriosis.(17) Dr Sanchez says that endocannabinoid system and receptors (CB1 and CB2 receptors, etc). play a regulatory role for the endometrium throughout the menstrual cycle are these same receptors are present in the endometriosis tissue implants ouside the uterus in the peritoneal cavity. These endocannabinoid receptors are also present in sensory and sympathetic nerves supplying the endometrial emplants.(17) Various medicinal cannabinoids are found to be beneficial for endometriosis, producing both a reduction of cellular proliferation, and control of pain symptoms. Conversely, endometrial cell migration tends to be stimulated by drugs that block endocannabinoid receptors in the endometrium. (17)
β-Caryophyllene – Potent CB2 Receptor Agonist
Caryophyllene is a natural comnonent of cannabis oil as well as Copaiba Oil, which contains a cyclobutane ring which is quite rare in nature. Beta-caryophyllene is bioavailable, non-toxic and serves as a potent activator of CB2 endocannabinoid receptor system. These are receptors are present in the peripheral tissues and the immune system.
Published in 2013 European Journal of Pharmacology, Dr. Abbas reported his study using β-Caryophyllene in a mouse model of endometriosis.(18) Dr Abbas found β-Caryophyllene, a natural plant oil causes regression of endometrial implants with preservation of fertility.
He found that: ” β-Caryophyllene suppressed growth of endometriotic implants by 52.5% compared with controls. Also β-caryophyllene produced apoptosis in luminal epithelim of the cyst as well as in endothelial cells of blood vessels.”
He concluded: ” Therapy with β-caryophyllene may present a promising novel, non-toxic therapeutic option for patients with endometriosis.”(18)
Milk Thistle, Curcumin and Berberine have been found beneficial in treatment of endometriosis, and adenomysis.(23-25)
Update 2014: November Issue of Dr Jonathan Wright’s newsletter discusses endometriosis. 1) Gluten Free Diet 2) HCG treatment.
In Huber’s 2004 study, 31 women with painful endometriosis refractory to therapoy were given HCG injections (1500-5000 iu per week) for 3-12 months with a highly significant reduction in endometriosis related pain.(19) Further studies on the mechanism by which HCG exerts its benefits performed by Dr Huber shows changes in gene expression by endometrial stromal cells induced by HCG treatment. His findings were validated in a later study.
Gluten Free Diet Beneficial for Endometriosis
Celiac disease incidence is increased among patients with endometriosis, and Gluten free diet was found beneficial in this report.(20-22)
Update 2016: Targeting the WNT pathway in Endometriosis
Update 2017: Fenofibrate Causes Regression of Endometriosis
Fertil Steril. 2009 Dec;92(6):2100-2. Epub 2009 Jul 5. Fenofibrate causes regression of endometriotic implants: a rat model.Onalan G1, Zeyneloglu HB, Bayraktar N. Fenofibrate -a peroxisome proliferator-activated receptor-a agonist- is an angiostatic agent that is commonly used in human liver diseases, therefore it may interfere with the angiogenetic process required for endometriosis. In a rat endometriosis model, we demonstrated that peritoneal implant areas and vascular endothelial growth factor levels in the peritoneal flud were significantly decreased in high dose or low dose finofibrate and luprolide acetate treated groups compared to control.
Update on Medical Treatment for Endometriosis by Kaur, Kulvinder Kochar, and Gautam Allahbadia. “An Update on Pathophysiology and Medical Management of Endometriosis.” Advances in Reproductive Sciences 4.02 (2016): 53.
Fenretinide: Vitamin A analog induces apoptosis in endometriosis and reduces lesion size in animal xenograft model, and may prove beneficial.(22)
Jeffrey Dach MD
74590 Griffin Road Suite 190
Davie, Florida 33314
Health, Risk & Society Volume 11, Issue 4, 2009 pages 367-385
Nobody really knows what it is or how to treat it’: Why women with endometriosis do not comply with healthcare advice Kate Seeara*
This paper examines the phenomenon of non-compliance with health advice among 20 women who have been diagnosed with a chronic and incurable gynaecological condition called endometriosis. Women’s non-compliance emerges out of their subjective experiences of self-care and risk-avoidance injunctions as burdensome and excessive, as well as practically impossible, time-consuming and too expensive. Non-compliance is also motivated by a desire to avoid exposure to potential risks that can arise from compliance itself. Women also resist risk-avoidance advice on the basis of their scepticism and mistrust of doctors, whose expertise about endometriosis they doubt. This analysis contributes to our understanding of patient non-compliance and has ramifications for how health promotion and risk-avoidance campaigns are constructed and implemented, especially where chronic illnesses are concerned.
Indian J Med Res. Jun 2011; 133(6): 581–593.
Endometriosis, a modern syndrome. by Ivo Brosens and Giuseppe Benagiano Leuven Institute for Fertility & Embryology, Leuven, Belgium Department of Gynaecology, Obstetrics & Urology, ‘Sapienza’ University of Rome, Italy
Front Biosci (Schol Ed). 2014 Jan 1;6:16-28.
Menstrual endometrial supernatant may induce stromal endometriosis in baboons. Kyama CM1, Falconer H2, Cuneo S2, Chai D2, Mihalyi A1, Mwenda J2, D’Hooghe T3.
We tested the hypothesis that endometriosis can be induced in baboons more successfully by intra-pelvic injection of the pellet of menstrual endometrium when compared to its supernatant. Menstrual endometrium, separated into pellet (n = 5) and supernatant fractions ( n = 8), or phosphate buffered saline (1 ml, n = 7, controls) was injected laparoscopically into the pelvis. During laparoscopy 25 days later, the number (ρ = 0.027) and surface area (ρ <0.0001) of endometriosis-like lesions were significantly higher in the pellet group, than in the supernatant group, or in the control group. Histological typical endometriosis was present only in the endometrial pellet group (1/15), whereas stromal endometriosis was observed in both the pellet group (6/15), and the supernatant group (6/20). Peritoneal endometrial like glands were observed in both the endometrial pellet group (3/15), and in the supernatant group (1/20). In conclusion, we confirmed our hypothesis that endometriosis can be induced in baboons more successfully by intrapelvic injection of the pellet of menstrual endometrium when compared to its supernatant.
Wideochir Inne Tech Malo Inwazyjne. Jun 2012; 7(2): 122–131.
Pericardial, pleural and diaphragmatic endometriosis in association with pelvic peritoneal and bowel endometriosis: a case report and review of the literature. Marcello Ceccaroni,corresponding author1,2 Giovanni Roviglione,1,2 Piergiorgio Rosenberg,3 Anna Pesci,4 Roberto Clarizia,1,5 Francesco Bruni,1,2 Claudio Zardini,6 Giacomo Ruffo,6 Angelo Placci,7 Stefano Crippa,6 and Luca Minelli2
Reproduction March 1, 2004 127 293-304
Endometriosis and the neoplastic process by Rajesh Varma1,2, Terrance Rollason3, Janesh K Gupta2 and Eamonn R Maher. Section of Medical and Molecular Genetics, 2Academic Department of Obstetrics and Gynaecology and 3Department of Histopathology, Birmingham Women’s Hospital, Birmingham B15 2TG, UK.
Although endometriosis is a benign disorder, recent studies of endometriosis suggest endometriosis could be viewed as a neoplastic process.
In summary, there is extensive clinicopathological, molecular and genetic evidence supporting the hypothesis that endometriosis is a neoplastic process with a potential for malignant transformation.
endometriosis False positive PET scan
Eur J Obstet Gynecol Reprod Biol. 2004 Dec 1;117(2):236-9.
Endometriosis with FDG uptake on PET.
Jeffry L1, Kerrou K, Camatte S, Metzger U, Lelièvre L, Talbot JN, Lecuru F. The value of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in endometriosis has not yet been extensively reported.
CASE REPORT:A 32-year-old woman was examined to find an explanation for right pelvic pain associated with right subcostal pain. A computerised tomography (CT) scan was compatible with a haemangioma or a focus of endometriosis in the liver. Transvaginal sonography and magnetic resonance imaging (MRI) showed a complex ovarian cyst on the left. Blood CA125 levels were elevated. FDG-PET revealed a focus of uptake in the right paravesical area. Laparoscopy showed a left endometrioma associated with diffuse inflammatory pelvic adhesions. After surgery and 3 months GnRH agonist treatment the pain had disappeared and neither MRI nor FDG-PET showed any pelvic abnormality. The patient subsequently presented with dyspareunia and rectal pain resulting from a right uterosacral nodule and a rectal nodule. These were resected laparoscopically. After a 1-year follow-up, the patient is doing well.
CONCLUSION: Endometriosis can give rise to false-positive results on FDG-PET. However, the FDG uptake in this particular case of endometriosis seems to have been due to inflammation rather than to a cyst. This report highlights the relationship between some of the biological features of endometriosis and some observed in neoplastic lesions.
Resveratrol – ECGC (maybe Pterstilnbene)
Hum Reprod. 2013 Jan;28(1):178-88. doi: 10.1093/humrep/des369. Epub 2012 Oct 18. Natural therapies assessment for the treatment of endometriosis. Ricci AG1, Olivares CN, Bilotas MA, Bastón JI, Singla JJ, Meresman GF, Barañao RI.
Can resveratrol and epigallocatechin-3-gallate (EGCG) inhibit the growth and survival of endometriotic-like lesions in vivo in a BALB/c model of endometriosis, and in vitro in primary cultures of human endometrial epithelial cells (EECs)?
SUMMARY ANSWER:Resveratrol and EGCG exerted a potent inhibitory effect on the development of endometriosis in a BALB/c murine model and on the survival of EECs.
WHAT IS KNOWN ALREADY:Endometriosis is a common condition associated with infertility and pelvic pain in women of reproductive age. Resveratrol and EGCG are two polyphenols with anticarcinogenic and antioxidant properties that have been proposed as natural therapies to treat endometriosis.
STUDY DESIGN, SIZE, DURATION: Fifty-six 2-month-old female BALB/c mice underwent surgical induction of endometriosis. Treatments with resveratrol or EGCG started 15 days post-surgery and continued for 4 weeks. Human biopsies were taken with a metal Novak curette from the posterior uterine wall from 16 patients with untreated endometriosis and 15 controls who underwent diagnostic laparoscopy for infertility.
MATERIALS, SETTING, METHODS: After the treatments, animals were sacrificed and lesions were counted, measured, excised and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for cell proliferation and vascularization assessment in the lesions. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique was performed for apoptosis evaluation. Peritoneal fluid was collected to analyze vascular endothelial growth factor levels. Human EECs were purified from proliferative-phase endometrial biopsies and cultured. The effect of both polyphenols on cell proliferation was determined by a colorimetric assay using the CellTiter 96®AQueous One Solution Cell Proliferation Assay kit and on apoptosis by the TUNEL technique, using an In Situ Cell Death Detection Kit with Fluorescein.
MAIN RESULTS: In the mouse model, both treatments significantly reduced the mean number (P < 0.05 versus control) and the volume of established lesions (P < 0.05 versus control). Treatments consistently statistically significantly diminished cell proliferation (resveratrol P < 0.01 and EGCG P < 0.05, versus control), reduced vascular density (resveratrol P < 0.01 and EGCG P < 0.001, versus control) and increased apoptosis within the lesions (resveratrol P < 0.01 and EGCG P < 0.05, versus control). Both compounds induced reduction in human EEC proliferation (P < 0.05 versus basal) and increased apoptosis (P < 0.05 versus basal) in primary cultures.
LIMITATIONS: In vitro studies were only carried out in epithelial cells from human eutopic endometrium.
WIDER IMPLICATIONS OF THE FINDINGS: The present findings are promising and will assist the development of novel natural treatments for endometriosis.
STUDY FUNDING: This study was supported by ANPCYT (PICT 6384 BID 1201 OC-AR) and CONICET (PIP 5471), Argentina. None of the authors has any conflict of interest to declare.
Endometriosis is one of the most common benign disorders and affects 6–10% of women of reproductive age (Giudice and Kao, 2004). The disease is defined as the presence of endometrial glands and stroma outside the uterine cavity and patients with endometriosis often suffer from dysmenorrhea, dyspareunia, dysuria and chronic abdominal or pelvic pain, as well as infertility, resulting in a limited quality of life (Giudice and Kao, 2004). As the disease is estrogen-dependent, medical therapies are principally aimed at down-regulating ovarian estrogen production (Valle and Sciarra, 2003; Mihalyi et al., 2006).
EGCG from green tea and resveratrol from red wine and grapes are some of the natural options that have lately been considered to treat different types of cancer
We observed that both resveratrol and EGCG exerted a significant inhibition on the development of endometriotic-like lesions, reducing the size of the lesions, by diminishing cell proliferation and increasing apoptotic levels. Moreover, both treatments were able to decrease the number of established lesions per mouse. It is remarkable that a treatment that begins 15 days after surgery can affect the development and maintenance of already established endometriotic-like lesions rather than just their establishment.
Biol Reprod. 2011 Jan;84(1):106-12. Epub 2010 Sep 15.
Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro.
Bruner-Tran KL1, Osteen KG, Taylor HS, Sokalska A, Haines K, Duleba AJ.
Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17β-estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10-12 and 18-20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10-30 μM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis.
Fertil Steril. PMC Feb 1, 2014. Fertil Steril. Feb 2013; 99(2): 543–550.e1. Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model. Jennifer L. Herington, Ph.D.,a Dana R. Glore, B.S.,a John A. Lucas, M.D.,a Kevin G. Osteen, Ph.D.,a,b and Kaylon L. Bruner-Tran, Ph.D.a
Fertil Steril. 2008 Apr;89(4):934-42. Epub 2007 Jun 19.
Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Güney M1, Oral B, Karahan N, Mungan T.
To determine the antioxidant, antiinflammatory, and immunomodulatory effects of melatonin on endometrial explants, the distribution of cyclooxygenase-2 (COX-2), the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and levels of malondialdehyde (MDA) in the rat endometriosis model.
DESIGN:Prospective, placebo-controlled experimental study.
SETTING:Experimental surgery laboratory in a university department.
ANIMAL(S):Twenty-five rats with experimentally induced endometriosis.
INTERVENTION(S):Endometriosis was surgically induced in 25 rats by transplanting an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. Four weeks later, three rats were killed and the remaining 22 rats given second-look laparotomies to identify and measure ectopic uterine tissue in three dimensions. After the second laparotomy, 4 weeks of vehicle and melatonin treatment were administered, then all of the rats were given a third laparotomy and killed.
MAIN OUTCOME MEASURE(S):The volume and weight of the implants were measured. The remaining rats were randomly divided into two groups. In control group (group 1; n = 11) no medication was given. To the rats in melatonin-treated group (group 2; n = 11), 10 mg/kg a day of melatonin was administered intraperitoneally. Four weeks later, after the second laparotomy, the endometrial explants were reevaluated morphologically, and COX-2 expression was evaluated immunohistochemically and histologically. In addition, endometrial explants were analyzed for the antioxidant enzymes SOD, CAT, and MDA, a marker of lipid peroxidation. A scoring system was used to evaluate expression of COX-2 and preservation of epithelia.
RESULT(S):The pretreatment and posttreatment volumes within the control group were 135.9 +/- 31.5 and 129.4 +/- 28.7, respectively. The mean explant volume was 141.4 +/- 34.4 within the melatonin group before the treatment and 42.9 +/- 14.0 after 4 weeks of treatment. There was a statistically significant difference in spherical volumes (129.4 +/- 28.7 versus 42.9 +/- 14.0 mm(3)) of explant weights (155.8 +/- 27.1 versus 49.6 +/- 19.5 mg) and COX-2 positivity (91% versus 18.1%) between groups after the third laparotomy. In the melatonin-treated group, the endometrial explant levels of MDA statistically significantly decreased and activities of SOD and CAT significantly increased when compared with the control group. The epithelia showed statistically significantly better preservation in the control group when compared with the melatonin-treated group (2.54 +/- 0.52 versus 0.63 +/- 0.50). CONCLUSION(S):Melatonin causes regression and atrophy of the endometriotic lesions in rats.
Molecular Mechanisms of reveratrol
Crit Rev Food Sci Nutr. 2009 Oct;49(9):782-99. Fighting cancer with red wine? Molecular mechanisms of resveratrol.
Kraft TE1, Parisotto D, Schempp C, Efferth T.
Resveratrol, a red wine constituent, has been known for its cardioprotective effects. Recent data give ample evidence that resveratrol can act as a chemopreventive agent as well. Tumor initation, promotion, and progression are affected by resveratrol via multiple pathways, which are discussed in this review. Resveratrol has anti-inflammatory effects by counteracting NF-kappa B and AP-1 transcription and can prevent bioactivation of procarcinogens by interacting with drug metabolizing enzymes. Furthermore, resveratrol exerts antioxidant activities, hence contributing to the prevention of tumor initiation. Growing or metastasizing carcinomas are inhibited by resveratrol through prevention of angiogenesis by inhibiting VEGF and matrix metalloproteases. Induction of apoptosis and cell cycle arrest, important mechanisms for cancer therapy, are stimulated by resveratrol through different mechanisms, e.g., activation of p53 and modulation of cell cycle proteins. Although there has been remarkable evidence for resveratrol as a potent chemopreventive agent in vitro, it seems that the low bioavailability of resveratrol in humans could interfere with a successful in vivo treatment. Nevertheless, resveratrol offers two major advantages over conventional chemotherapy. The cytotoxic effects of resveratrol on healthy cells can be neglected, and, as several pathways leading to chemotherapeutic effects are activated by resveratrol, chemoresistance-inducing mutations in cancer cells can be overcome.
Adv Clin Chem. 2011;53:155-77.
EGCG, green tea polyphenols and their synthetic analogs and prodrugs for human cancer prevention and treatment.
Chen D1, Wan SB, Yang H, Yuan J, Chan TH, Dou QP.
Cancer-preventive effects of tea polyphenols, especially epigallocatechin-3-gallate (EGCG), have been demonstrated by epidemiological, preclinical, and clinical studies. Green tea polyphenols such as EGCG have the potential to affect multiple biological pathways, including gene expression, growth factor-mediated pathways, the mitogen-activated protein kinase-dependent pathway, and the ubiquitin/proteasome degradation pathway. Therefore, identification of the molecular targets of EGCG should greatly facilitate a better understanding of the mechanisms underlying its anticancer and cancer-preventive activities. Performing structure-activity relationship (SAR) studies could also greatly enhance the discovery of novel tea polyphenol analogs as potential anticancer and cancer-preventive agents. In this chapter, we review the relevant literature as it relates to the effects of natural and synthetic green tea polyphenols and EGCG analogs on human cancer cells and their potential molecular targets as well as their antitumor effects. We also discuss the implications of green tea polyphenols in cancer prevention.
Possible Loss of GABAergic Inhibition in Mice With Induced Adenomyosis and Treatment With Epigallocatechin-3-Gallate Attenuates the Loss With Improved Hyperalgesia. Reproductive Sciences February 3, 2014 . Yumei Chen, MD1 Bo Zhu, MD1 Hongping Zhang, MD1 Ding Ding, MD, PhD2 Xishi Liu, MD, PhD2 Sun-Wei Guo, PhD2⇑ 1Department of Obstetrics and Gynecology, The People’s Hospital, Wenzhou, Zhejiang, China
2Shanghai OB/GYN Hospital, Fudan University, Shanghai, China
Sun-Wei Guo, Shanghai Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011, China.
Abstract We have previously reported that induction of adenomyosis in mice results in progressive hyperalgesia, uterine hyperactivity, and elevated plasma corticosterone levels and that epigallocatechin-3-gallate (EGCG) treatment dose dependently suppressed myometrial infiltration and improved generalized hyperalgesia. In this study, we examined whether adenomyosis induced in mice results in the loss of GABAergic inhibition as manifested by the diminished glutamate decarboxylase (GAD) 65-expressing neurons in the brainstem nucleus raphe magnus (NRM) that could correlate with heightened hyperalgesia. We also evaluated whether EGCG treatment would reverse these changes and also improve the expression of some proteins known to be involved in adenomyosis. Adenomyosis was induced in 28 female ICR mice and additional 12 were used as blank controls, as reported previously. At the 16th week, all mice with induced adenomyosis received low- or high-dose EGCG treatment or untreated. Mice without adenomyosis received no treatment. After 3 weeks of treatment, their uterine horns and brains were harvested. The right uterine horn was used for immunohistochemistry analysis and for counting the number of macrophages infiltrating into the ectopic endometrium. The brainstem NRM sections were subjected to immunofluorescence staining for GAD65. We found that mice with induced adenomyosis had significantly diminished GAD65-expressing neurons, concomitant with heightened hyperalgesia. Treatment with EGCG increased these neurons in conjunction with improved hyperalgesia, reduced the expression of p-p65, cycloxygenase 2, oxytocin receptor, collagen I and IV, and transient receptor potential vanilloid type 1 in ectopic endometrium or myometrium, reduced the number of macrophages infiltrating into the ectopic endometrium while elevated the expression of progesterone receptor isoform B. Thus, adenomyosis-induced pain resembles neuropathic pain in that there is a remarkable central plasticity.
Reprod Sci. 2013 Dec;20(12):1478-91. Epub 2013 May 23.
Epigallocatechin-3-gallate reduces myometrial infiltration, uterine hyperactivity, and stress levels and alleviates generalized hyperalgesia in mice induced with adenomyosis.
Chen Y1, Zhu B, Zhang H, Liu X, Guo SW.
In an effort to search for novel therapeutics for adenomyosis, we sought to determine whether treatment with epigallocatechin-3-gallate (EGCG) would suppress the myometrial infiltration, improve pain behavior, lower stress level, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 28 female ICR mice neonatally dosed with tamoxifen, while another 12 (group C) were dosed with solvent only, which served as a blank control. Starting from 4 weeks after birth, hot plate test was administrated to all mice every 4 weeks. At the 16th week, all mice induced with adenomyosis were randomly divided into 3 groups: low-dose EGCG (5 mg/kg), high-dose EGCG (50 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, the hot plate test was administered again, a blood sample was taken to measure the plasma corticosterone level by enzyme-linked immunosorbent assay, and then all mice were sacrificed. The depth of myometrial infiltration and uterine contractility were also evaluated. We found that the induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and frequency of uterine contractions as well as elevated plasma corticosterone levels. The EGCG treatment dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels. These results suggest that induced adenomyosis causes pain and elevates stress levels in mice. Uterine hyperactivity may contribute to dysmenorrhea in women with adenomyosis who might also have elevated stress level due to pain. The EGCG appears to be a promising compound for treating adenomyosis.
Medical Cannabis for Endometriosis
Endocannabinoisd System in Endometriosis
Pain. 2010 Dec;151(3):703-10. doi: 10.1016/j.pain.2010.08.037. Epub 2010 Sep 15. Endocannabinoid involvement in endometriosis.
Dmitrieva N1, Nagabukuro H, Resuehr D, Zhang G, McAllister SL, McGinty KA, Mackie K, Berkley KJ.
Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain.
Herein, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments.
First, CB1 receptors were abundantly found not only on sensory and sympathetic fibers that had sprouted to innervate the ectopic growths (cysts), but also on retrogradely-identified somata of DRG and CG neurons from which the sprouted fibers originate. This finding indicates that CB1 receptors are strategically located for endogenous cannabinoids to influence functioning of cyst-innervating neurons. Second, CB1 labeling was significantly denser in the cysts than in the eutopic uterus. This finding indicates an upregulation of CB1 receptors in the ectopic uterine tissue relative to the healthy uterine tissue, which suggests that the endocannabinoid system is involved in the development and functioning of the abnormal sprouted innervation.
Fertil Steril. Oct 2012; 98(4): 948–956.e1.
Progesterone-dependent Regulation of Endometrial Cannabinoid Receptor Type 1 (CB1-R) Expression is Disrupted in Women with Endometriosis and in Isolated Stromal Cells Exposed to TCDD (2,3,7,8-tetrachlorodibenzo-p-
David Resuehr, PhD, Dana R. Glore, BS, Hugh S. Taylor, MD, PhD,† Kaylon L. Bruner-Tran, PhD, and Kevin G. Osteen, PhD
Women’s Reproductive Health Research Center, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN USA
†Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven CT, USA
To whom correspondence and reprint requests should be addressed: Kevin G. Osteen, PhD Women’s Reproductive Health Research Center Department of Obstetrics and Gynecology Vanderbilt University School of Medicine 1161 21st Ave S; MCN B-1100 Nashville, TN 37232
Conclusions:Our studies reveal a role for the anti-inflammatory actions of progesterone in regulating endometrial cannabinoid signaling, which is disrupted in women with endometriosis. Significantly, our studies demonstrate, for the first time, that acute TCDD exposure disrupts cannabinoid signaling in the human endometrium.
Endometriosis, characterized by the presence of endometrial glands and stroma at extrauterine sites, is a common and debilitating reproductive disease of uncertain etiology. Although typically considered an endocrine disorder, women with endometriosis frequently exhibit immune system dysfunctions that not only affect the initial development of the disease but may contribute to the impaired fertility and severe pelvic pain that are frequently noted as co-morbidities [1–2]. Although estrogen has long been considered to represent the most important steroid in the pathogenesis of endometriosis [2–3], research over the past decade suggests that reduced progesterone sensitivity may play an equally relevant role in the initiation and progression of this disease [4–7].
Based on a review of evidence from multiple laboratories, we recently proposed that exposure to dioxin-like environmental toxicants, including 2,3,7,8-tetrachlorodibenzo-p-
The molecular connections between the cannabinoid system and endometriosis A.M. Sanchez1,P. Vigano2,*, A. Mugione1, P. Panina-Bordignon1 and M. Candiani2 1Reproductive Sciences Laboratory, Obstetrics and Gynecology Unit, San Raffaele Scientific Institute, Milan, Italy
The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid 1 (CB1) and 2 (CB2) receptors. Alterations of this system have been described in almost every category of disease. These changes can be protective or maladaptive, making the endocannabinoid network an attractive therapeutic target. Little is known about the potential role of endocannabinoids in endometriosis development although this is a topic worthy of further investigation since endocannabinoid modulators have recently been shown to affect specific mechanisms critical to endometriosis establishment and maintenance. A literature review was herein performed with the aim of defining the regulation and function of the endocannabinoid signaling in in vitro and animal models of endometriosis. The components of the endocannabinoid system, CB1 and CB2 receptors and the enzymes N-
The endocannabinoid system and endometriosis-related pain
Endometriosis is usually associated with pelvic pain such as chronic dysmenorrhea, intermenstrual abdominal and pelvic pain, back pain, dysuria, dyschezia and dyspareunia.
The neural mechanisms of pain in endometriosis have been extensively described elsewhere (Stratton and Berkley, 2011). Three mechanisms, nociceptive, inflammatory and neuropathic, seem to be relevant to endometriosis-associated pelvic pain (Howard, 2009).
These findings suggest that cannabinoids could suppress endometriosis-induced hyperalgesia via the CB1 receptor (Dmitrieva et al., 2010). A promising new direction for developing new treatments for pain suffered by women with endometriosis may arise from these data.
β-Caryophyllene constituent of essential oil of Cannabis sativa,
Eur J Pharmacol. 2013 Feb 28;702(1-3):12-9. doi: 10.1016/j.ejphar.2013.01.011. Epub 2013 Jan 23.
β-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility.
Abbas MA1, Taha MO, Zihlif MA, Disi AM.
Many studies have shown that anti-inflammatory agents are effective in the treatment of endometriosis. β-Caryophyllene exerted a potent anti-inflammatory effect in vivo. However, its effect on endometriosis has not been investigated. This study aims at investigating the effect of β-caryophyllene on endometriosis and on fertility and reproduction in adult female rats.
Autologous fragments of the endometrium were implanted in the peritoneal cavity in adult female rats. The growth of the endometriotic implants that developed after four weeks was recorded. Treatment started then with β-caryophyllene (10 mg/kg or 30 mg/kg) or vehicle (control) for 21 days and the growth of the endometriotic implants was measured again. In fertility studies, female rats that received β-caryophyllene or vehicle were mated and reproductive functions were observed including number and viability of implants, number of corpora lutea, length of pregnancy and outcome of litter.
β-Caryophyllene (10 mg/kg) suppressed the growth of endometriotic implants by 52.5% compared with controls. Also β-caryophyllene produced apoptosis in luminal epithelim of the cyst as well as in endothelial cells of blood vessels. Ultrastructural studies revealed the presence of active mast cells and eosinophils in both control and β-caryophyllene-treated rat cysts. No statistically significant difference was observed in any studied parameter between control and β-caryophyllene-treated groups in fertility study. Therapy with β-caryophyllene may present a promising novel, non-toxic therapeutic option for patients with endometriosis.
Ambros V. Huber, Johannes C. Huber, Andrea Kolbus, Martin Imhof, Fritz Nagele, Demosthenes Loizou, Ulrike Kaufmann, and Christian F. Singer Systemic HCG treatment in patients with endometriosis: A new perspective for a painful disease. Wien Klin Wochenschr 2004;116/24:839-843 (Weiner Klinische Wochenschrift, the Middle European Journal of Medicine, printed in Austria)
Gluten Free Diet for Endometriosis
20) Stephansson O, Falconer H, Ludvigsson JF. Risk of endometriosis in 11,000 women with celiac disease. Human Reproduction 2011;26(10):2896-2901
Marziali M, Vemza M, Lazzaro S et al. Gluten-free diet: a new strategy for management of painful endometriosis related symptoms? Minerva Chirurgica 2012;67(6):499-504
22) Fenretinide A Potential Treatment for Endometriosis
Pavone, Mary Ellen, et al. “Fenretinide: a potential treatment for endometriosis.” Reproductive Sciences 23.9 (2016): 1139-1147.
Fenretinide is a synthetic retinoid analogue that promotes apoptosis but has decreased toxicity when compared to other retinoids. We have previously shown that retinoic acid (RA) production in endometriotic tissue is decreased, resulting in reduced estrogen metabolism and apoptotic resistance. We hypothesize fenretinide may induce apoptosis in endometriotic cells and tissues, thereby reducing disease burden.
Materials and Methods: Primary endometriotic stromal cells were collected, isolated, cultured, and treated with fenretinide in doses from 0 to 20 µmol/L. Cell count, viability, and immunoblots were performed to examine apoptosis. Quantitative reverse transcription-polymerase chain reaction from endometriotic cells treated with fenretinide was used to examine expression of genes involved in RA signaling including stimulated by RA 6 (STRA6), cellular RA binding protein 2 (CRABP2), and fatty acid binding protein 5 (FABP5). Endometriotic tissue was xenografted subcutaneously into the flanks of mice which were treated with fenretinide for 2 weeks, after which the mice were killed and lesion volumes calculated. Statistical analysis was performed using t test and analysis of variance.
Results: Treatment with fenretinide significantly decreased total cell count (doses 5-20 µL) and viability (doses 10-20 µmol/L). Fenretinide increased protein levels of the apoptotic marker poly (ADP ribose) polymerase (starting at 10 µmol/L) and decreased proliferation marker proliferating cell nuclear antigen (10 µmol/L, starting at 8-day treatment). Examination of genes involved in retinoid uptake and action showed that treatment induced STRA6 expression while expression of CRABP2 and FABP5 remained unchanged. Fenretinide also significantly decreased the endometriotic lesion xenograft volume.
Conclusions: Fenretinide increases STRA6 expression thereby potentially reversing the pathological loss of retinoid availability. Treatment with this compound induces apoptosis. In vivo treatments decrease lesion volume. Targeting the RA signaling pathway may be a promising novel treatment for women with endometriosis.
Milk Thistle for Endometriosis
23) J Cell Physiol. 2019 Apr;234(4):4327-4341. Silibinin-induced endoplasmic reticulum stress and mitochondrial dysfunction suppress growth of endometriotic lesions. Ham J1, Kim J1, Bazer FW2, Lim W3, Song G1.
Silibinin is a flavonolignan extracted from milk thistle, which has been used for treating liver disorders, various cancers, and gynecological diseases. However, attempts for treating endometriosis with silibinin are lacking. In this study, we observed that silibinin exerts antiproliferative and apoptotic effects on human endometriotic cell lines VK2/E6E7 and End1/E6E7. We also identified that silibinin-induced oxidative stress and lipid peroxidation in human endometriotic cells. Moreover, we observed upregulation of calcium concentration in the cytosol and mitochondrial matrix, which resulted in mitochondrial dysfunction. Furthermore, induction of endoplasmic reticulum stress signals with rapid mitogen-activated protein kinase (MAPK) pathway signaling resulted in apoptosis of both cells. Using an animal model mimicking the retrograde menstruation hypothesis, we verified the effects of silibinin on reducing endometriotic lesions by inhibiting the expression of inflammatory cytokines in mice. Silibinin might be used as a novel therapeutic agent or supplement for inhibiting progression of endometriosis in vitro and in vivo.
Curcumin for Endometriosis
24) Cao, Hong, et al. “Inhibitory effect of curcumin in human endometriosis endometrial cells via downregulation of vascular endothelial growth factor.” Molecular medicine reports 16.4 (2017): 5611-5617.
Endometriosis, which affects up to 10% of women of reproductive age, is defined as endometrial-like gland and stroma tissue growths outside the uterine cavity. Despite increasing research efforts, there are no current effective treatment methods for this disease, therefore investigations for therapeutic strategies are of primary concern. In preliminary work, the authors demonstrated that curcumin inhibits endometriosis in vivo. The present in vitro study aimed to investigate the association between endometriotic stromal cells and curcumin and to clarify the underlying mechanism of action. A total of 14 patients with endometriosis were enrolled in the present study. The purity of endometrial stromal cell cultures was proven by standard immunofluorescent staining of vimentin. The cell proliferation and curcumin effects on endometrial stromal cells were assessed by the MTT assay and Hematoxylin and Eosin staining. For cell cycle analysis, phase distribution was detected by flow cytometry. Vascular endothelial growth factor (VEGF) protein expression was examined using immunohistochemistry staining. Apoptosis was assessed using Annexin V‑fluorescein isothiocyanate staining. The results indicated that the treatment of curcumin decreased human ectopic and eutopic stromal cell growth. Following treatment with curcumin, human endometriotic stromal cells demonstrated an increased percentage of G1‑phase cells and decreased percentages of S‑phase cells, particularly in the group treated with 50 µmol/l curcumin. Treatment with curcumin additionally decreased expressi
on of VEGF. The data provide evidence that curcumin reduces cell survival in human endometriotic stromal cells, and this may be mediated via downregulation of the VEGF signaling pathway.
25) Liu, Li, et al. “Berberine inhibits the LPS‑induced proliferation and inflammatory response of stromal cells of adenomyosis tissues mediated by the LPS/TLR4 signaling pathway.” Experimental and therapeutic medicine 14.6 (2017): 6125-6130.
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