Nearly 2 years ago we reported the first study on the association between resveratrol and endometriosis, the disease involving most frequently pelvic pain and infertility (1). The preliminary tests (2) on mice showed that the organic antioxidant poliphenol might have application in therapy of endometriosis. This devious disease seems to escape every treatment option, so the prospect was more than promising. Today we see that resveratrol has come up to our expectations. A group of Brazilian scientists conducted an interesting clinical trial (3) investigating the impact of resveratrol added to conventional oral contraceptives on pain level. In addition the researchers examined the expression of aromatase (enzyme responsible for aromatization of androgens into estrogens) and cyclo-oxygenase-2 in the endometrial tissue. Both tests provide encouraging results.
Patophysiology of endometriotic lesions
Endometriosis is defined as a presence of ectopic endometrial tissue. The implants of endometrium are under a constant influence of sex hormones. In fact, endometriotic lesions seem to show their own estradiol (E2) biosynthesis, which is higher than in normal endometrium (4). However, therapies of endometriosis-related pain, which lower the concentration of circulating E2, like oral contraceptives, GnRH analoges or danazol, are successful in less than half of the patients. It may be explained by the fact that patients suffering from endometriosis present an increased expression of genes for steroidogenic acute regulatory protein (StAR) and aromatase, which are both essential for E2 production. It has been observed that in endometriosis the production of prostaglandin E2 (PGE2), greatest known stimulator of StAR and aromatase, is up-regulated because of the increased levels of the enzyme cyclo-oxygenase-2 (COX-2) in the lesions. COX-2 in turn is stimulated by E2, interleukin-1beta and PGE2 itself. As we see, there is a positive feedback loop that favours continuous formation of E2 and PGE2 in endometriosis. Resulting from it increased oxidatory stress and high concentration of inflammatory mediators might be responsible for pain and infertility in endometriosis. In order to treat it one would have to stop this self- propelled mechanism.
Utilizing resveratrol’s biologic properties
Currently, various combinations of drugs are tested for inhibition of aromatase in endometriosis patients. For example, it was found that oral contraceptives containing gestodene are effective in decreasing aromatase expression in the eutopic endometrium (5). The synthetic progestin dienogest, the revelation of this year, is also supposed to inhibit the expression of aromatase, as well as COX-2 and PGE2 (6). However, hormone therapy tends to have various side effects that limits the spectrum of its application. What is the place of resveratrol in this story? Growing evidence indicates that resveratrol possesses anti-neoplastic, anti-inflammatory and antioxidant properties.(2) In vitro and in vivo it shows growth-inhibiting and apoptosis-inducing activities.(2) At pharmacological doses resveratrol inhibits aromatase activity at both enzyme and gene transcription levels (7) This polyphenol is naturally synthesized by plants like grapes, berries and nuts. It is also found in high concentrations in red wine. No side-effects are known, as this compound is registered only as a dietary supplement, which makes it a candidate for natural, long-term, side-effect-free endometrosis therapy.
Reversing the pain scale
The office-based part of the highlighted study was designed to evaluate the effect of resveratrol on the management of endometriosis-related pain in women using an oral contraceptive (drospirenone 3 mg + ethinylestradiol 30 µg). Authors of the study speculate that in these patients who did not respond fully to the contraceptive therapy, resveratrol might come in handy. The facts quoted by them show that resistance to oral contraceptive treatment might be associated with high levels of aromatase expression in the endometriotic lesions (8). They place emphasis on the notion that level of aromatase expression in the lesions, but also in the eutopic tissue, determine the aggressiveness of the disease (9). A combination of an oral contraceptive pill with synthetic aromatase inhibitors seemed beneficial (8), so with resveratrol being the natural representative of the above-mentioned, success could be also achieved. Indeed, the addition of 30 mg/day resveratrol resulted in a significant reduction in questionnaire-based pain scores after 2 months of treatment. 82% of the patients reported complete resolution of dysmenorrhea and pelvic pain.
Detection of the villainous enzyme
In the second part of the study, the effect of resveratrol on aromatase and cyclo-oxygenase-2 expression in the eutopic endometrium was investigated in patients with pelvic pain and/or infertility qualified to laparoscopy and hysteroscopy. Some had been using contraceptives for at least 2 months prior to surgery while some had been taking the same contraceptive associated with 30 mg of resveratrol daily. Additional data was obtained from a few patients in the resveratrol group who had been submitted to a pretreatment endometrial biopsy for aromatase expression. Immunohistochemistry for aromatase and COX-2 expression was performed in all biposies. Results show that 68% of patients in the drospirenone + ethinylestradiol group demostrated a positive reaction for aromatase in the endometrial glands with only 19% in the resveratrol group. According to the obtained data, the staining reaction for aromatase was positive in all cases before the treatment with resveratrol, but only in 1 case following the therapy. As far as COX-2 expression is concerned, in the contraceptive-only group none of the samples tested negative, whereas in the resveratrol group 43% didn’t show any staining reaction.
Booster for contraceptives
As we see, resveratrol has lived up to scientists’ expectations. In combination with oral contraceptives, it decreases the aromatase and COX-2 expression, which may lead to the dropping of estrogen levels and hampering the inflammation. These processes probably cause the alleviation of endometriosis-related pain, which along with infertility, is the biggest issue for sufferers. Application of a small dose of a safe substance, for a short period of time, resulted in dramatic changes in the biochemistry of endometrium and comfort of patients. Although the tests are still preliminary, having involved a small group of subjects, I believe that the community of endometriosis patients will show enthusiasm for these news. As resveratrol is available in the pharmacies off the counter, women can find on their own if this poliphenol is truly as miraculous as described.
Written by: Natalia Neumann
Source:
1.Neumann N. Resveratrol hamuje endometriozę w warunkach eksperymentalnych. http://medtube.pl/tribune-pl/2010/12/resveratrol-hamuje-endometrioze-w-warunkach-eksperymentalnych/
2.Bruner-Tran KL, Osteen KG, Taylor HS et al. Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro. Biol Reprod. 2011 Jan;84(1):106-12. doi: 10.1095/biolreprod.110.086744. Epub 2010 Sep 15.
3.Maia H Jr, Haddad C, Pinheiro N et al. Advantages of the association of resveratrol with oral contraceptives for management of endometriosis-related pain. Int J Womens Health. 2012;4:543-9. doi: 10.2147/IJWH.S36825. Epub 2012 Oct 10
4.Attar E, Bulun SE. Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum Reprod Update. 2006 Jan-Feb;12(1):49-56. Epub 2005 Aug 25.
5.Maia H Jr, Casoy J, Correia T et al. The effect of oral contraceptives on aromatase expression in the eutopic endometrium of patients with endometriosis. Gynecol Endocrinol. 2008 Mar;24(3):123-8. doi: 10.1080/09513590801890816.
6.Yamanaka K, Xu B, Suganuma I, Kusuki I et al. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E₂ production in human endometriotic stromal cells in spheroid culture. Fertil Steril. 2012 Feb;97(2):477-82. doi: 10.1016/j.fertnstert.2011.11.005. Epub 2011 Nov 30.
7.Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic disease. Cell Cycle. 2008;7:1020–1035
8.Amsterdam LL, Gentry W, Jobanputra S et al. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril. 2005;84:300–304.
9.Hatok J, Zubor P, Galo S, et al. Endometrial aromatase mRNA as a possible screening tool for advanced endometriosis and adenomyosis. Gynecol Endocrinol. 2010;27:331–336.
Would You like to know more? Watch on MEDtube.net: Laparoscopy For Endometriosis