To the best of our knowledge, this is the first double-blind, randomized clinical trial conducted to investigate the effect of silymarin on IL-6, endometrioma volume, QoL, pain, and sexual function in women diagnosed with OMA.
Ovarian endometriotic cyst affects 17–44% of women suffering of endometriosis and it per se and its surgical treatment could impair ovarian function, ovarian reserve by significant reduction in serum Anti-Mullerian Hormone (AMH) and in Antral Follicle Count (AFC), pregnancy outcomes, and on IVF/ICSI outcomes (36).
The exact physiopathology of endometriosis is not clarified. Inflammation, however, is known as a main factor in initiation and progression of endometriosis. Hence, inflammatory mediators such as IL-1β, IL‐6, IL‐8 increase in the peritoneal, serum, and endometrium of endometriosis patients, leading to enhancing proliferation and decreasing apoptotic rate in endometriotic cells (37, 38). In addition, the expression of Cyclooxygenase‐2 (COX‐2), Vascular Endothelial Growth Factor (VEGF), IL‐6, Tumor Necrosis Factor‐α (TNF‐α), IL‐8, C‐C Motif Chemokine 2 (MCP‐1), and IL‐10 have increased in endometriosis cases (39, 40).
Several papers have investigated that oxidative stress plays a vital role in endometriosis pathophysiology as iron overload and inflammation can have impacts on the mechanism of oxidative stress (41, 42). ROS concentration promotes fibrogenic response, collagen matrix remodeling, and fibrosis (36). Sanchez et al. showed that endometrioma cysts contain ROS, free iron, inflammatory molecules, and proteolytic enzymes in concentrations hundred times higher than those present in peripheral blood or in other types of benign cysts (2).
Additionally, dysregulations in angiogenesis and apoptosis pathways might be contributed in endometriosis pathophysiology (43). Furthermore, the advanced endometriosis may lead to gynecological malignancies and infertility (43). For instance, the increased risk of developing ovarian cancer is proved by somatic mutations of PIK3CA, PTEN, and ARID1A in endometriosis patients especially in younger ones, however the absolute higher risk is not completely clear (44). Ideally, therapeutic strategies to conquer endometriosis should be done regarding theses pathogeneses.
Silymarin is one of the highly potent antioxidant agents that inhibits lipid peroxidation and exerts antioxidant (45, 46). In addition, its anti-inflammatory, antifibrotic, immunomodulatory, and membrane-stabilizing effects have broadly confirmed through numerous studies (47, 48). This study was conducted to investigate the effect of Silymarin on IL-6, endometrioma volume, quality of life, pain, and sexual function in women diagnosed with endometriosis.
This study confirms that silymarin can be effective in reducing endometrioma lesions is consistent with previous observations in animal models.
Jouhari et al. compared the effects of silymarin, Cabergoline, and Letrozole on induced endometrial lesions in rats for about 6 months. Silymarin, Letrozole, and Cabergoline administration could decrease size and histopathologic grade of the induced endometrial lesions significantly and those who were received silymarin had significantly higher serum total antioxidant activity compared to control after 21 days (21).
Nahari et al. evaluating legions establishment and growth in experimentally-induced endometriosis in 12 rats after 28 days of oral administration of silymarin showed that the combination of enhancing ERK1/2 expression and suppressing the Bcl-2 expression by silymarin accompanying with down-regulating the angiogenesis ratio led to promote the apoptosis pathway, consequently induced severe fibrosis in endometriotic-like legions (22).
A recent prospective study showed that not only could silibinin induce oxidative stress and lipid peroxidation in human endometriotic cells, but also it exerted antiproliferative and apoptotic impacts on human endometriotic cell lines VK2/E6E7 and End1/E6E7. Moreover, the effects of silibinin on reducing endometriotic lesions by inhibiting the expression of inflammatory cytokines was verified by using an animal model mimicking the retrograde menstruation hypothesis in mice and they proved the possibility of effectiveness of silibinin as a novel therapeutic agent or supplement in inhibiting progression of endometriosis in vitro and in vivo (23).
The present results showed that oral administration of silymarin 280 mg/day decreased the IL-6 levels significantly during the study period within the intervention group. Arafa Keshk et al. evaluating the potential protective effects of silymarin against indomethacin-induced gastric injury in rats, have demonstrated that suppression in gastric inflammation by decreasing myeloperoxidase activity, TNF- α, and IL-6 levels along with Nuclear Factor Kappa B p65 (NF-κB) expression was observed. Meanwhile, silymarin prevent gastric oxidative stress via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up-regulation of Nuclear Factor-Erythroid-2-Related Factor 2 (Nrf2), the redox-sensitive master regulator of oxidative stress signaling (49).
Additionally, Wei Zhang et al. showed that silymarin could protect against the liver injury caused by ethanol administration as it markedly downregulated the expression of NF-κB p65, ICAM-1 and IL-6 in liver tissue (50).
Rongjuan Zheng et al. evaluated the chemo-preventive effect of silibinin (major component of silymarin) on a Colitis-Associated Cancer (CAC) mouse model and determined its impact on IL-6/STAT3 signaling. Silibinin decreased the amount and size of tumors in mice accompanying with inhibition of colonic tumor cell proliferation and promotion of cellular apoptosis. Furthermore, they showed that silibinin could reduce the production of inflammatory cytokines and can protect against colitis-associated tumorigenesis in mice via inhibiting IL-6/STAT3 (51).
In addition, it is revealed that silymarin attenuate the expression of NF-kB and the subsequent inflammatory cascade by suppressing IκB, effectively can down-regulate the expressions of TPA-induced IL-1β, IL-6, TNF-α, and COX-2 in a dose-dependent manner (52, 53).
Pain- related symptoms
Numerous mechanisms are involved in endometriosis-related pain such as various algogens (pain-producing agents), cytokines (such as IL-1b, IL-6, and TNF-a), growth factors (such as b-nerve growth factor and vascular endothelial growth factor), and several chemokines, such as CCL2 (54, 55).
Several papers have investigated that different kind of antioxidant such as vitamin E and vitamin C can reduce peritoneal inflammatory markers and decrease chronic pelvic pain in endometriosis women (56–58). It might be speculated silymarin could be effective in reducing pain as it can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration (59, 60). This study supports evidence from previous observations about the analgesic effects of silymarin.
Vahdati Hassani et al. investigating the effects of silymarin in both chemical nociception and neuropathic pain in rats, showed that silymarin administer was significantly effective in preventing the formalin-induced nociceptive behavior, while it did not have significant effects in reducing sciatic neuropathic pain (61).
Quality of life and sexual function
Endometriosis is a very complex condition with wide range of clinical features including pelvic pain, dyspareunia, infertility, and menstrual irregularities that might compromise QoL, psychological wellbeing, sexual function, and interpersonal relationships of affected women (62, 63).
Caruso et al. evaluating the effects of dienogest on QoL and sexual function in endometriosis women, reported that progressive reduction of the pain could contribute in improving the QoL and sexual life (64).
Very little was found in the literature on the question of the effectiveness of silymarin on QoL and sexual function. Gillessen et al. investigating the effect of silymarin on liver function and QoL in a non-interventional study, reported that improvement in liver-related symptoms and increased QoL after 2 months (65).
Previous researches had proved that silymarin and other anti-oxidants agents can enhance QoL in patients because of their positive effects on pain reduction (66, 67). However, the present study found inconsistent results and there was neither a significant difference in SF-12 between treatment and placebo groups nor within groups pre/post treatment
The strengths of the study are the RCT design and novelty. In addition, as maintaining endometriosis associated women on a placebo is unethical, the intervention was recommended along with routine treatment. However, the principal limitation of the study is the 8% loss to follow-up and the short duration of follow-up; therefore, results probably cannot be extrapolated for long-term treatment. Additionally, these data warrant further investigations for the potential use of silymarin in the management of endometriosis features to assess long-term effects of this treatment by larger sample.