Laparoscopic Surgery and Pentoxifylline: Endometriosis-related Infertility
Laparoscopic Surgery and Pentoxifylline: Endometriosis-related Infertility
Background: Surgical treatment has modest efficacy for the treatment of infertility associated with early-stage endometriosis. Immunomodulation with pentoxifylline is considered as a new strategy potentially useful in treating endometriosis. Thus, this study investigated the usefulness of combined laparoscopic surgery and pentoxifylline therapy in the treatment of infertility associated with minimal to mild endometriosis.
Methods: A prospective, randomized, controlled blind trial was conducted. Patients entered the study immediately after laparoscopic surgery and were randomly assigned to the treatment with either oral pentoxifylline (800 mg/day) (pentoxifylline group, n = 51) or an oral placebo (placebo group, n = 53). Patients were then observed for pregnancy for 6 months.
Results: Among 98 patients finally considered in the evaluation of the results, the 6 month overall pregnancy rates were 28 and 14% in the pentoxifylline and placebo groups, respectively. Thus, an absolute difference of 14% (95% CI –2 to 30) (Chi-squared test, P = 0.1) in the cumulative probability of pregnancy in 6 months after laparoscopic surgery in patients receiving pentoxifylline versus placebo post-operatively was observed.
Conclusion: Our findings provide preliminary clinical evidence to suggest the new experimental treatment approaches, toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute our results.
Current guidelines for the treatment of stages I-II endometriosis-associated infertility recommend ablation of endometriosis lesions plus adhesiolysis to improve fertility (Kennedy et al., 2005; The Practice Committee of the American Society for Reproductive Medicine, 2006). This recommendation is based on a meta-analysis of two similar but contradictory randomized controlled trials investigating the effect on pregnancy rates of surgical ablation or resection of the endometriosis lesions (Marcoux et al., 1997; Parazzini, 1999). When the results of the two studies were combined, the absolute treatment difference was 8%, yielding a number needed to treat of 12, thus indicating that for every 12 women undergoing laparoscopy that have ablation of minimal or mild endometriosis lesions, there will be one additional pregnancy, compared with not doing ablation. Thus, it was concluded that there is a statistical evidence for a slight beneficial effect of surgical removal of the lesions, but the size of this effect is small and may be short-lived (ESHRE Capri Workshop Group, 2004).
The modest efficacy of minimal to mild endometriosis ablation in increasing the pregnancy rate in infertile women may be explained by the fact that the surgical treatment can remove visible lesions but will leave behind a number of occult ones, which, after removal of the visible lesions, may develop into minimal endometriosis and proceed from there (Evers, 2004). This would explain why the optimal time for conception to occur is within the first months following surgical resection (Silverberg, 1992; Donnez et al., 2003). On the other hand, considering that the monthly fecundity rate among women who underwent laparoscopic surgery is lower than the rate expected in fertile women, it must be assumed that the destruction of visible endometriotic implants do not affect all factors by which minimal and mild endometriosis contributes to infertility (Marcoux et al., 1997). In other words, it is possible that the visible lesions contribute only a small fraction of the reduced fecundity seen in women with early-stage endometriosis (The Practice Committee of the American Society for Reproductive Medicine, 2006).
On the above evidence, combined therapy involving surgical excision of visible endometriosis followed by the administration of ovulation-suppression hormones to treat potential residual lesions has been extensively used (Winkel, 1999; The Practice Committee of the American Society for Reproductive Medicine, 2006). The goal is similar to that commonly applied in then treatment of ovarian cancer, i.e. cytoreductive surgery followed by chemotherapy. By definition, however, post-operative hormone therapy in patients with endometriosis prevents attempts at conception during what may be the optimal time for conception to occur following surgery. Therefore, a surgical and post-operative medical therapy combined approach avoiding ovulation suppression would be warranted for treatment of endometriosis-associated infertility. In fact, the need for clinical trials assessing potential new medical treatments combined with surgical therapies has been recently stressed (Olive, 2003; Guidice and Kao, 2004; Olive et al., 2004).
It is now generally accepted that the immune system is involved in the pathogenesis of endometriosis. Although the peritoneal fluid of women with endometriosis contains increased numbers of immune cells, these facilitate rather than inhibit the development of endometriosis. Also, endometriotic lesions secrete several proinflammatory molecules and the pelvic inflammation in women with endometriosis contributes to the development of their most common complaints, pain and infertility (Nothnick, 2001; Seli and Arici, 2003; Guidice and Kao, 2004). Thus, the use of general immunomodulators is considered as a new strategy potentially useful in endometriosis (Nothnick, 2001; Nothnick and D’Hooghe, 2003; Olive, 2003; Olive et al., 2004). In fact, early experimental work showed that immunomodulation affects both endometriotic implant growth and endometriosis-associated infertility (Steinleitner et al., 1991a,b,c; Nothnick et al., 1994; Keenan et al., 1999; Badawy et al., 2001), but available data in the clinical setting are limited and indefinite (Balasch et al., 1997; Alborzi et al., 2007).
Therefore, this prospective, randomized clinical study was undertaken to investigate the usefulness of combined laparoscopic surgery and pentoxifylline therapy for the treatment of early-stage endometriosis-associated subfertility.
Background: Surgical treatment has modest efficacy for the treatment of infertility associated with early-stage endometriosis. Immunomodulation with pentoxifylline is considered as a new strategy potentially useful in treating endometriosis. Thus, this study investigated the usefulness of combined laparoscopic surgery and pentoxifylline therapy in the treatment of infertility associated with minimal to mild endometriosis.
Methods: A prospective, randomized, controlled blind trial was conducted. Patients entered the study immediately after laparoscopic surgery and were randomly assigned to the treatment with either oral pentoxifylline (800 mg/day) (pentoxifylline group, n = 51) or an oral placebo (placebo group, n = 53). Patients were then observed for pregnancy for 6 months.
Results: Among 98 patients finally considered in the evaluation of the results, the 6 month overall pregnancy rates were 28 and 14% in the pentoxifylline and placebo groups, respectively. Thus, an absolute difference of 14% (95% CI –2 to 30) (Chi-squared test, P = 0.1) in the cumulative probability of pregnancy in 6 months after laparoscopic surgery in patients receiving pentoxifylline versus placebo post-operatively was observed.
Conclusion: Our findings provide preliminary clinical evidence to suggest the new experimental treatment approaches, toward endometriosis, that are based on immunomodulation deserve further attention. Well-designed multicenter trials are warranted to confirm or refute our results.
Current guidelines for the treatment of stages I-II endometriosis-associated infertility recommend ablation of endometriosis lesions plus adhesiolysis to improve fertility (Kennedy et al., 2005; The Practice Committee of the American Society for Reproductive Medicine, 2006). This recommendation is based on a meta-analysis of two similar but contradictory randomized controlled trials investigating the effect on pregnancy rates of surgical ablation or resection of the endometriosis lesions (Marcoux et al., 1997; Parazzini, 1999). When the results of the two studies were combined, the absolute treatment difference was 8%, yielding a number needed to treat of 12, thus indicating that for every 12 women undergoing laparoscopy that have ablation of minimal or mild endometriosis lesions, there will be one additional pregnancy, compared with not doing ablation. Thus, it was concluded that there is a statistical evidence for a slight beneficial effect of surgical removal of the lesions, but the size of this effect is small and may be short-lived (ESHRE Capri Workshop Group, 2004).
The modest efficacy of minimal to mild endometriosis ablation in increasing the pregnancy rate in infertile women may be explained by the fact that the surgical treatment can remove visible lesions but will leave behind a number of occult ones, which, after removal of the visible lesions, may develop into minimal endometriosis and proceed from there (Evers, 2004). This would explain why the optimal time for conception to occur is within the first months following surgical resection (Silverberg, 1992; Donnez et al., 2003). On the other hand, considering that the monthly fecundity rate among women who underwent laparoscopic surgery is lower than the rate expected in fertile women, it must be assumed that the destruction of visible endometriotic implants do not affect all factors by which minimal and mild endometriosis contributes to infertility (Marcoux et al., 1997). In other words, it is possible that the visible lesions contribute only a small fraction of the reduced fecundity seen in women with early-stage endometriosis (The Practice Committee of the American Society for Reproductive Medicine, 2006).
On the above evidence, combined therapy involving surgical excision of visible endometriosis followed by the administration of ovulation-suppression hormones to treat potential residual lesions has been extensively used (Winkel, 1999; The Practice Committee of the American Society for Reproductive Medicine, 2006). The goal is similar to that commonly applied in then treatment of ovarian cancer, i.e. cytoreductive surgery followed by chemotherapy. By definition, however, post-operative hormone therapy in patients with endometriosis prevents attempts at conception during what may be the optimal time for conception to occur following surgery. Therefore, a surgical and post-operative medical therapy combined approach avoiding ovulation suppression would be warranted for treatment of endometriosis-associated infertility. In fact, the need for clinical trials assessing potential new medical treatments combined with surgical therapies has been recently stressed (Olive, 2003; Guidice and Kao, 2004; Olive et al., 2004).
It is now generally accepted that the immune system is involved in the pathogenesis of endometriosis. Although the peritoneal fluid of women with endometriosis contains increased numbers of immune cells, these facilitate rather than inhibit the development of endometriosis. Also, endometriotic lesions secrete several proinflammatory molecules and the pelvic inflammation in women with endometriosis contributes to the development of their most common complaints, pain and infertility (Nothnick, 2001; Seli and Arici, 2003; Guidice and Kao, 2004). Thus, the use of general immunomodulators is considered as a new strategy potentially useful in endometriosis (Nothnick, 2001; Nothnick and D’Hooghe, 2003; Olive, 2003; Olive et al., 2004). In fact, early experimental work showed that immunomodulation affects both endometriotic implant growth and endometriosis-associated infertility (Steinleitner et al., 1991a,b,c; Nothnick et al., 1994; Keenan et al., 1999; Badawy et al., 2001), but available data in the clinical setting are limited and indefinite (Balasch et al., 1997; Alborzi et al., 2007).
Therefore, this prospective, randomized clinical study was undertaken to investigate the usefulness of combined laparoscopic surgery and pentoxifylline therapy for the treatment of early-stage endometriosis-associated subfertility.
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