O-134 Cochrane review on the effect of pentoxifylline for endometriosis

Abstract

Study question To assess the effect of pentoxifylline, a methyl-xanthine with anti-inflammatory effects, for the management of premenopausal women with endometriosis. Summary answer There is not enough evidence to support the use of pentoxifylline in the management of premenopausal women with endometriosis to improve fertility and pain outcomes. What is known already Endometriosis is a chronic, inflammatory condition that occurs mainly during the reproductive years. It is characterized by endometrium-like tissue developing outside the uterine cavity. This endometriotic tissue development is dependent on estrogen produced primarily by the ovaries and partially by the endometriotic tissue itself and, therefore, hormonal management is traditionally used. In light of the body of evidence suggesting an immunological component to the pathophysiology of endometriosis, the anti-inflammatory agent pentoxifylline has been proposed as an alternative therapeutic agent. Study design, size, duration A Cochrane systematic review and meta analysis was performed. Electronic searches of the Cochrane Gynaecology and Fertility Specialised Register of Controlled Searches, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL and AMED OVID were conducted to December 2020 to identify relevant randomised controlled trials (RCTs). In addition, electronic searches were conducted on the Epistemonikos database, Human Reproduction, Web of Knowedlge, OpenGrey, LILACS, Pubmed and Google. Participants/materials, setting, methods Participants: premenopausal women with endometriosis via laparoscopy/laparotomy. For extent of endometriosis, grades according to the AFS/rASRM scoring system were used. Intervention: pentoxifylline treatment for any period of time Comparisons: placebo, no treatment, medical treatment, surgical treatment. Two independent authors screened studies and extracted data. Risk ratios were calculated for dichotomous data (Peto odds ratio for low event rates) and mean differences (MD) for continuous data, with 95% confidence intervals (CI). Main results and the role of chance Five RCTs were included, involving 415 participants. Pentoxifylline vs placebo No trials reported on live birth or reduction of pain. We are uncertain whether pentoxifylline affects the clinical pregnancy rate (Peto OR 1.53, 95% CI 0.89 to 2.63; 3 RCTs, n = 285; I2 = 0%; very low-quality evidence), recurrence rate (Peto OR 0.83, 95% CI 0.26 to 2.60; 1 RCT, n = 121; very low-quality evidence), or miscarriage rate (Peto OR 1.99, 95% CI 0.20 to 19.37; 2 RCTs, n = 164; I2= 0%; very low-quality evidence). Pentoxifylline vs no treatment We are uncertain whether pentoxifylline impacts on pain reduction when compared to no treatment at one month (MD -0.36, 95% CI -2.08 to 1.36; 1 RCT; n = 34; very low-quality evidence), two months (MD -1.25, 95% CI -2.67 to 0.17; 1 RCT; n = 34; very low-quality evidence) or three months (MD -1.60; 95% CI -3.32 to 0.12; n = 34; very low-quality evidence). No studies reported on live birth. Pentoxifylline vs medical treatment One study compared pentoxifylline with the combined contraceptive pill, but could not be included in the meta-analysis, as it was unclear if the data were presented as +/- standard deviation. Pentoxifylline vs surgical treatment No study reported on this comparison Limitations, reasons for caution Based on the GRADE criteria, the quality of evidence was classified as very low with issues arising due to risk of bias and imprecision. Four studies did not apply the intention-to-treat principle. None of the studies reported on live birth rate, one of the primary outcomes of the review. Wider implications of the findings Future research should prioritise live birth and overall pain as the primary outcome and include patients with all endometriosis severity types. All included studies compared pentoxifylline with placebo or no treatment after surgery, which highlights the need for more types of comparisons, such as to hormonal contraception. Trial registration number Not applicable

Effects of pentoxifylline and metformin combination therapy compared to metformin alone in infertile women with symptomatic endometrioma

“…3.12±1.42 cm in metformin alone, p=0.012s) aligns with the broader narrative in endometriosis management, where combination therapies often outperform single-agent treatments, as suggested by Taniguchi et al 25 However, the non-significant differences in VAS score and IL-6 levels post-treatment (VAS: p=0.188ns, IL-6: p=0.147ns) present a more nuanced picture, indicative of the multifaceted nature of endometriosis symptomatology and its management, resonating with findings by Grammatis et al 26 The pregnancy rates observed in our study, 8% in the pentoxifylline plus metformin group versus 3.85% in the metformin alone group, did not show a significant difference (p=0.610ns). This finding is in line with Balasch et al and Gardezi et al where treatment modalities did not significantly impact fertility outcomes.…”

Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

“…PDE4B is mainly present in immune and epithelial cells and has a role modulating inflammation and epithelial integrity. 83 Considering current evidence for Pentoxifylline, which was used to treat endometriosis by targeting PDE4B encoded protein, 53 this study provides some evidence for the further investigation of PDE4B for the purpose of treating both endometriosis and GI disorders.…”

“…Compared with IBS, which has multiple sources of evidence to support the promising treatment effect of Pentoxifylline, 51 , 52 there is limited evidence on whether Pentoxifylline impacts endometriosis related pain reduction. 53 …”

Evidence of shared genetic factors in the aetiology of gastrointestinal disorders and endometriosis and clinical implications for disease management

“…Therefore, the involvement of gastrin and CCKBR in estrogen metabolism may implicate this gene as a potential drug target for endometriosis. Moreover, considering the low quality of current evidence for Pentoxifylline which was used to treat endometriosis by targeting PDE4B encoded protein 53 , this study provides more evidence and novel insight for the further investigation of PDE4B for the purpose of treating both endometriosis and GI disorders.…”

“…In addition, PDE4B with its encoded protein cAMP-specific 3',5'-cyclic phosphodiesterase 4B being targeted by Pentoxifylline, acts as an inhibitor targeting the immune system and has been clinically trialled for the treatment of both endometriosis (phase III) and IBS (Phase IV) separately (Table 6). Compared with IBS which has multiple sources of evidence to support the promising treatment effect of Pentoxifylline 51 52 , there is limited evidence on whether Pentoxifylline impacts endometriosis related pain reduction 53 . Notably, when not restricted to the aforementioned gene set, 34 genes with encoded proteins were targets of both endometriosis and IBS/GORD/PUD drugs (Supplementary Table 13).…”