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Surgery versus pharmacological treatment for endometriosis Sarit Avraham1 & Daniel S Seidman*1 The two major consequences of endometriosis are pain and infertility. Despite numerous studies and proposed guidelines, some aspects of the treatment for these complications are still under debate or lack convincing evidence that favors one approach over the other. Future studies will hopefully present new evidence in regard to the optimal treatment for each indication and suggest innovative pharmacotherapy following improved understanding of the pathophysiology of endometriosis. Until then, individualization of the treatment according to the specific indication, taking into consideration the benefits versus the risks for the patient and the tolerability profile, remains the most appropriate approach.
Issues to address
Endometriosis is a chronic inflammatory dis order that involves extrauterine endometrial tissue, which responds to estrogen stimulation. The main adverse consequences attributed to endo metriosis are pain and infertility. Pain manifestations vary from dysmenorrhea, chronic pelvic pain and dyspareunia to dyschezia and dysuria [1,2]. Endometriosis-related infertility has been attributed to many possible mechanisms, including decreased endometrial receptivity, impaired tubal function, impaired oocyte and embryo development, and physical block of the fallopian tubes [3]. The high prevalence of endometriosis, up to 10% in the general female population and up to 50% among symptomatic women [4], has resulted, over the years, in a vast research effort with regard to the optimal treatment of endometriosis-related symptoms. However, the multiplicity of different protocols and guidelines indicate that there are still many controversies to settle, and innovative treatments are still sought. A major concern among the scientific society was raised in regard to a possible lack of transparency in clinical trials on endometriosis [5]. Despite the mandatory registration of clinical trials [6], in less than a third of the trials completed by late 2012 were results published, and data from trials that were sponsored by the pharmaceutical industry were nearly four-times less likely to be published compared with nonindustry-sponsored trials. Moreover, the publication rate of endometriosis clinical studies was significantly lower than that of completed nonendometriosis registered trials. Diagnosis & staging
The definite diagnosis of endometriosis requires histological confirmation of macroscopic lesions 10.2217/WHE.13.77 © 2014 Future Medicine Ltd
identified and removed during surgery. The histologic correlation varies in different reports due to diverse appearance, different stages and the pelvic anatomy [7,8]. The detection rates were suggested to be increased with the use of advanced laboratory stain techniques, and well informed and trained pathologists. The most widely used staging system is the revised American Society for Reproductive Medicine classification, based on anatomic location, depth and size of the lesions, and the presence of adhesions. It allows uniform staging and research result comparison, but does not correlate well with clinical symptoms or pregnancy outcomes following treatment [9]. Recently, the Endometriosis Fertility Index has been validated as a predictor of pregnancy rates in nonassisted reproductive technology [10], and might be of clinical use in the future. Treatment for pain Pharmacological treatment
NSAIDs inhibit the production of prostaglandins, which are responsible for pain sensation, and are prescribed by many clinicians for endometriosis-related pain due to their high availability and low cost (Table 1). However, the latest Cochrane analysis identified only two randomized controlled trials (RCTs) that compared NSAIDs to placebo for endometriosis-related pain, and only one was considered methodologically reliable [11]. The remaining article showed no benefit of NSAIDs over placebo for pain relief, the use of additional analgesia or side effects, but was too small to supply a conclusive recommendation. The next commonly used pharmacological group for pain treatment in endometriosis are hormonal agents, which suppress the influence Women's Health (2014) 10(2), 161–166
Department of Obstetrics & Gynecology, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel *Author for correspondence: Tel.: +972 52 6666 437 Fax: +972 3 604 4146 [email protected] 1
Keywords • dysmenorrhea • endometrioma • endometriosis • infertility • pelvic pain • selective progesterone receptor modulators
part of
ISSN 1745-5057
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perspective – Avraham & Seidman Table 1. Profile of the main treatments for endometriosis. Treatment Advantages
Disadvantages
NSAIDs
Adverse effects with No role long-term use
No proven efficacy over placebo
Hormonal Proven efficacy suppression
Adverse effects with Benefit in pre-ART long-term use treatment High relapse rate
Effective for pain palliation
Dienogest
Improved safety profile
Expensive
Effective for pain palliation
Surgery
Avoids the adverse effects associated with hormonal suppression
High recurrence rate Proven Surgery-related effectiveness only complications for minimal mild endometriosis Limited benefit and potential harm with endometrioma excision
High availability Low cost
Infertility
No role
Pain
Effective for pain palliation Improved life quality Improved sexual function
ART: Assisted reproductive technologies.
of sex steroids on endometriosis lesions, such as gonadotropin-releasing hormone (GnRH) agonists and different progestogens. A recent update concluded that all commonly used hormonal agents have demonstrated effectiveness in endometriosis pain alleviation with no superiority of a specific agent [12]. Preference should consider safety and adverse effect profiles, including possible loss of bone mineral density with longterm use of GnRH agonists [13]. Combined oral contraceptive pills also demonstrated efficacy in suppressing implants and endometriomas, and achieving effective pain relief in a several studies, but have a high relapse rate after therapy completion [13–15]. Modern delivery systems, such as the vaginal ring and the transdermal patch, demonstrated similar results in pain relief, but were associated with reduced patient adherence and bleeding control, in addition to a relatively higher cost [16]. Dienogest is a new selective progestin that lacks androgenic, mineralocorticoid and glucocorticoid activity, and was shown to be more effective than placebo for reducing endometriosis-associated pelvic pain [17]. In a randomized, multicenter study, dienogest was compared with leuprolide acetate in women with endometriosis [18,19] and displayed noninferiority to leuprolide acetate in treating endometriosis symptoms. It also demonstrated specific quality-of-life benefits, such as satisfaction with work productivity and energy level, and better safety profile. The levonorgestrel intrauterine system, labeled as a contraceptive and a heavy menstrual bleeding treatment, showed effectiveness in reducing endometriosis lesion severity and the size of rectovaginal lesions [20,21]. A multicenter RCT 162
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demonstrated that the levonorgestrel intrauterine system was as effective as the GnRH analog for the treatment of endometriosis-related pain, with avoidance of hormonal suppression [22]. It also seems, according to recent accumulating data, to reduce the recurrence of painful periods in women undergoing surgical treatment for endometriosis [23]. Ongoing research, focused on not yet fully understood pathophysiology of endometriosis, aims to find new targets for the treatment of endometriotic tissue. These studies include animal models, which demonstrate a potential of antioxidant molecules and specific intracellular pathway inhibitors, such as antiproliferative and inhibitors of endometriotic lesions [24,25]. Further research might allow alternative treatments (e.g., specific pathway inhibitors) to the current hormonal therapies. Surgical treatment
Surgical management of endometriotic lesions may have the potential for definitive cure while avoiding the side effects of prolonged medical treatment. A recent update summarized results from noncomparative studies in regard to outcomes of surgery for endometriosis-related pelvic pain [26]. Most studies demonstrated improvement in menstrual and nonmenstrual pain, dyspareunia and life quality postsurgery, but with recurrence rates of up to 54% and repetitive surgery risk, particularly in young women. The latest Cochrane meta-analysis assessed the efficacy of laparoscopic surgery in treatment of endometriosis-related pelvic pain, as studied in RCTs [27]. The analysis highlighted improved pain outcomes when compared with diagnostic future science group
Surgery versus pharmacological treatment for endometriosis –
laparoscopy alone, but no conclusions could be drawn in regard to severe endometriosis treatment or specific surgical interventions. Moreover, there were no published RCTs that compared effectiveness of surgery versus medical treatment for pain associated with endometriosis. A global consensus meeting held in 2011, in conjunction with the World Congress on Endometriosis in France, gathered opinions of 56 representatives and published a statement on the current management of endometriosis [28]. In regard to surgical management of endometriosis symptoms, it was agreed that appropriate surgical expertise and adequate technical resources were crucial aspects when planning surgery. It was stated that laparoscopic surgery should always be preferred over laparotomy, particularly in the case of severe endometriosis, and that excision, rather than ablation of endometriotic lesions, should be performed, although, superiority has not yet been proven in RCTs. There is some evidence that, in regard to deep dyspareunia, surgical treatment results in better outcomes and fewer side effects compared with medical treatment [29]. Women that underwent surgeries for excision of deep endometriotic lesions, including vaginal, rectal or sigmoid resection, experienced significant improvement in sexual functioning, quality of life and pelvic pain [30,31]. However, possible complications of extensive surgery must always be thoroughly discussed with the patient preoperatively. Surgical nerve interruption with laparoscopic uterine nerve ablation or laparoscopic presacral neurectomy, when combined with surgical treatment for endometriosis implants, have so far gained limited evidence supporting their use [32]. The addition of laparoscopic uterine nerve ablation displayed no additional benefit in pain relief while presacral neurectomy, although being found to have an overall difference in pain relief, might be specific for midline abdominal pain only and had significantly more adverse events. Treatment for infertility Pharmacological treatment
No evidence of fertility improvement was shown with the use of different ovulation suppression agents or the anti-inflammatory pentoxifylline, in subfertile women with endometriosis who were interested in pregnancy [33–35]. On the contrary, women with endometriosis who underwent IVF may benefit from prolonged GnRH agonists administration before treatment [36], as well as from oral contraceptive pills administration for 6–8 weeks prior to treatment future science group
perspective
with assisted reproductive technologies [37]. IVF outcomes in women with endometriosis seem, overall, similar to outcomes among patients with other indications when controlled for age [38], despite earlier reports of reduced pregnancy rates when compared with other indications [38,39]. Superovulation with or without intra uterine insemination increases pregnancy rates in women with mild endometriosis [40], while IVF should be suggested as first-line treatment for women with more severe disease, particularly those with compromised tubal function [28]. Surgery
A meta-analysis of randomized trials demonstrated an advantage of laparoscopic surgery compared with diagnostic laparoscopy in the treatment of subfertile women with minimal and mild endometriosis in regard to clinical pregnancy rates [41]. Conservative surgery was also suggested as effective for natural conception during the first year after the operation [42]. Surgery for more severe disease lacks conclusive support from randomized trials. Controversy exists in regard to the influence of endometriomas on fertility, the response to IVF treatments, and the possible diminished ovarian reserve following endometrioma resection. In women with unilateral, unoperated endometriomas undergoing IVF, no statistically significant difference was shown between the two ovaries in regard to the number of cysts, their dimension, the dose of gonadotrophins used or the number of oocytes retrieved [43]. Another study showed that, in the case of bilateral endometriomas at the time of IVF, the oocyte quality and the chances for pregnancy were not affected despite reduced responsiveness to ovarian hyperstimulation [44]. A Cochrane analysis summarized that there was no evidence for improved clinical pregnancy rates with surgery versus expectant management among women with endometriomas undergoing IVF [45]. A greater concern was raised in regard to the potential harm to the ovarian reserve with removal of endometriomas. A case–control, retrospective study analyzed 428 first-attempt IVF cycles in women with ovarian endometriosis compared with patients with tubal infertility and found no difference in IVF outcomes [46]. However, patients who underwent ovarian surgery prior to IVF treatment had significantly lower antral follicle count and required higher gonadotropin doses. Garcia-Velasco and Somigliana concluded that since the association between endometriomarelated injury and surgery-mediated damage still needs to be clarified, and since surgery is not
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perspective – Avraham & Seidman risk-free, surgery should be indicated only in the presence of large cysts, concomitant refractory pain or in the case that malignancy could not be ruled out [47]. This notion was further supported in a systematic review that showed surgery-related damage to ovarian reserve with declined serum antimullerian hormone, particularly in women operated for bilateral endometriomas [48]. A recent prospective study suggested that the presence of endometrioma per se was related to reduced ovarian reserve, as reflected by lower antimullerian hormone levels [49]. Serum antimullerian hormone levels were further reduced following endometrioma excision and the decline rate positively correlated with preoperative levels. Although the natural decline in ovarian reserve due to endometrioma compared with surgery-related decline should be further investigated, these results raise the need to carefully consider when to delay or avoid excision once fertility is desired. Combined therapy
A review of randomized trials that evaluated the effectiveness of hormonal suppression before or after surgery for endometriosis in relation to pain symptoms, recurrence rates and pregnancy rates, supported earlier assessments that found no benefit associated with postsurgical medical therapy and insufficient evidence of benefit from
presurgical therapy, with regard to the outcomes evaluated [50]. Conclusion
Endometriosis-related pain can be addressed with either medical therapy or surgery. Although not proven in RCTs, NSAIDs are widely prescribed. Different hormonal suppression agents are effective for pain control, but should be monitored for side effects and have high relapse rates when withdrawn. Newer effective solutions, such as dienogest and the levonorgestrel system, offer a better safety profile. Laparoscopic surgery for pelvic pain displays an alternative to medical treatment, but was not proven to be superior to it. In any case, surgery should be performed by experts in the field. Infertility related to endometriosis can be addressed with surgery in mild-to-moderate disease. The role of surgery for severe endo metriosis-related infertility has not yet been proven. The handling of endometriomas is under an ongoing debate. Future perspective
A better understanding of the pathophysio logy of endometriosis may launch a new generation of pharmacotherapy targeted at specific intracellular pathways and mechanisms.
Executive summary Endometriosis is a common disorder & the search for the ideal solution continues • Endometriosis is a chronic disorder with up to 50% prevalence in symptomatic women. The two main complications related to endometriosis are pain and infertility. • There are a lack of transparent clinical data in regard to treatment of endometriosis-related complications. Pelvic pain in endometriosis can be addressed with either pharmacotherapy or surgery • NSAIDs are widely used for the treatment of endometriosis-related pain, but were not proven to be effective over placebo in randomized controlled trials. • Hormonal suppression treatment is effective for pain palliation with no superiority of a specific agent, but might exhibit adverse side effects with prolonged use and high relapse rate with discontinuation. • Dienogest was proven to be effective for pain relief with improved safety profile. • Laparoscopic surgery improves pain outcomes, and should be performed by experts in the field with consensus agreement towards excision rather than ablation. Surgery is effective but limited in the treatment of endometriosis-related infertility & should be individualized • There is no evidence for medical treatment for fertility improvement. • IVF should be offered as first-line therapy for women with severe disease, with benefit from hormonal suppression prior to treatment. • In randomized controlled trials, surgery for subfertility proved to be effective only for mild disease. • Excision of endometriomas in women who desire future fertility did not demonstrate effectiveness and was even suggested as harmful in regard to ovarian reserve. • There is no benefit in pre- or post-surgical medical therapy for pain, recurrence rates and pregnancy rates. Conclusion • From the evident data from the literature to date, no single approach is ideal for all women. Individualization of therapy should be made according to the major complaint and must balance efficacy, safety and tolerability profiles. Future perspective • Ongoing research on the intracellular pathways involved in endometriosis pathophysiology holds promise for effective treatment with fewer adverse effects.
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Surgery versus pharmacological treatment for endometriosis –
New selective progesterone receptor modulator drugs seem, at present, to hold the most immediate promise to offer endometriosis patients an effective medical treatment with few side effects. Well-controlled randomized, prospective trials are needed comparing medical treatment versus surgery for endometriosis-related pain and assessing the impact of endomerioma excision for women with endometriosis who desire fertility. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
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Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. management of endometriosis. Expert Opin. Pharmacother. 14(3), 291–305 (2013).
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Kössi J. Sexual functioning, quality of life and pelvic pain 12 month after endometriosis surgery including vaginal resection. Acta Obstet. Gynecol. Scand. 91(6), 692–698 (2012). 31. Kössi J, Setälä M, Mäkinen J, Härkki P,
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Growing role of antimullerian hormone in assessing ovarian reserve.
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operative medical therapy for endometriosis surgery. Cochrane Database Syst. Rev. 3, CD003678 (2004).
future science group
Surgery versus pharmacological treatment for endometriosis Sarit Avraham1 & Daniel S Seidman*1 The two major consequences of endometriosis are pain and infertility. Despite numerous studies and proposed guidelines, some aspects of the treatment for these complications are still under debate or lack convincing evidence that favors one approach over the other. Future studies will hopefully present new evidence in regard to the optimal treatment for each indication and suggest innovative pharmacotherapy following improved understanding of the pathophysiology of endometriosis. Until then, individualization of the treatment according to the specific indication, taking into consideration the benefits versus the risks for the patient and the tolerability profile, remains the most appropriate approach.
Issues to address
Endometriosis is a chronic inflammatory dis order that involves extrauterine endometrial tissue, which responds to estrogen stimulation. The main adverse consequences attributed to endo metriosis are pain and infertility. Pain manifestations vary from dysmenorrhea, chronic pelvic pain and dyspareunia to dyschezia and dysuria [1,2]. Endometriosis-related infertility has been attributed to many possible mechanisms, including decreased endometrial receptivity, impaired tubal function, impaired oocyte and embryo development, and physical block of the fallopian tubes [3]. The high prevalence of endometriosis, up to 10% in the general female population and up to 50% among symptomatic women [4], has resulted, over the years, in a vast research effort with regard to the optimal treatment of endometriosis-related symptoms. However, the multiplicity of different protocols and guidelines indicate that there are still many controversies to settle, and innovative treatments are still sought. A major concern among the scientific society was raised in regard to a possible lack of transparency in clinical trials on endometriosis [5]. Despite the mandatory registration of clinical trials [6], in less than a third of the trials completed by late 2012 were results published, and data from trials that were sponsored by the pharmaceutical industry were nearly four-times less likely to be published compared with nonindustry-sponsored trials. Moreover, the publication rate of endometriosis clinical studies was significantly lower than that of completed nonendometriosis registered trials. Diagnosis & staging
The definite diagnosis of endometriosis requires histological confirmation of macroscopic lesions 10.2217/WHE.13.77 © 2014 Future Medicine Ltd
identified and removed during surgery. The histologic correlation varies in different reports due to diverse appearance, different stages and the pelvic anatomy [7,8]. The detection rates were suggested to be increased with the use of advanced laboratory stain techniques, and well informed and trained pathologists. The most widely used staging system is the revised American Society for Reproductive Medicine classification, based on anatomic location, depth and size of the lesions, and the presence of adhesions. It allows uniform staging and research result comparison, but does not correlate well with clinical symptoms or pregnancy outcomes following treatment [9]. Recently, the Endometriosis Fertility Index has been validated as a predictor of pregnancy rates in nonassisted reproductive technology [10], and might be of clinical use in the future. Treatment for pain Pharmacological treatment
NSAIDs inhibit the production of prostaglandins, which are responsible for pain sensation, and are prescribed by many clinicians for endometriosis-related pain due to their high availability and low cost (Table 1). However, the latest Cochrane analysis identified only two randomized controlled trials (RCTs) that compared NSAIDs to placebo for endometriosis-related pain, and only one was considered methodologically reliable [11]. The remaining article showed no benefit of NSAIDs over placebo for pain relief, the use of additional analgesia or side effects, but was too small to supply a conclusive recommendation. The next commonly used pharmacological group for pain treatment in endometriosis are hormonal agents, which suppress the influence Women's Health (2014) 10(2), 161–166
Department of Obstetrics & Gynecology, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel *Author for correspondence: Tel.: +972 52 6666 437 Fax: +972 3 604 4146 [email protected] 1
Keywords • dysmenorrhea • endometrioma • endometriosis • infertility • pelvic pain • selective progesterone receptor modulators
part of
ISSN 1745-5057
161
perspective – Avraham & Seidman Table 1. Profile of the main treatments for endometriosis. Treatment Advantages
Disadvantages
NSAIDs
Adverse effects with No role long-term use
No proven efficacy over placebo
Hormonal Proven efficacy suppression
Adverse effects with Benefit in pre-ART long-term use treatment High relapse rate
Effective for pain palliation
Dienogest
Improved safety profile
Expensive
Effective for pain palliation
Surgery
Avoids the adverse effects associated with hormonal suppression
High recurrence rate Proven Surgery-related effectiveness only complications for minimal mild endometriosis Limited benefit and potential harm with endometrioma excision
High availability Low cost
Infertility
No role
Pain
Effective for pain palliation Improved life quality Improved sexual function
ART: Assisted reproductive technologies.
of sex steroids on endometriosis lesions, such as gonadotropin-releasing hormone (GnRH) agonists and different progestogens. A recent update concluded that all commonly used hormonal agents have demonstrated effectiveness in endometriosis pain alleviation with no superiority of a specific agent [12]. Preference should consider safety and adverse effect profiles, including possible loss of bone mineral density with longterm use of GnRH agonists [13]. Combined oral contraceptive pills also demonstrated efficacy in suppressing implants and endometriomas, and achieving effective pain relief in a several studies, but have a high relapse rate after therapy completion [13–15]. Modern delivery systems, such as the vaginal ring and the transdermal patch, demonstrated similar results in pain relief, but were associated with reduced patient adherence and bleeding control, in addition to a relatively higher cost [16]. Dienogest is a new selective progestin that lacks androgenic, mineralocorticoid and glucocorticoid activity, and was shown to be more effective than placebo for reducing endometriosis-associated pelvic pain [17]. In a randomized, multicenter study, dienogest was compared with leuprolide acetate in women with endometriosis [18,19] and displayed noninferiority to leuprolide acetate in treating endometriosis symptoms. It also demonstrated specific quality-of-life benefits, such as satisfaction with work productivity and energy level, and better safety profile. The levonorgestrel intrauterine system, labeled as a contraceptive and a heavy menstrual bleeding treatment, showed effectiveness in reducing endometriosis lesion severity and the size of rectovaginal lesions [20,21]. A multicenter RCT 162
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demonstrated that the levonorgestrel intrauterine system was as effective as the GnRH analog for the treatment of endometriosis-related pain, with avoidance of hormonal suppression [22]. It also seems, according to recent accumulating data, to reduce the recurrence of painful periods in women undergoing surgical treatment for endometriosis [23]. Ongoing research, focused on not yet fully understood pathophysiology of endometriosis, aims to find new targets for the treatment of endometriotic tissue. These studies include animal models, which demonstrate a potential of antioxidant molecules and specific intracellular pathway inhibitors, such as antiproliferative and inhibitors of endometriotic lesions [24,25]. Further research might allow alternative treatments (e.g., specific pathway inhibitors) to the current hormonal therapies. Surgical treatment
Surgical management of endometriotic lesions may have the potential for definitive cure while avoiding the side effects of prolonged medical treatment. A recent update summarized results from noncomparative studies in regard to outcomes of surgery for endometriosis-related pelvic pain [26]. Most studies demonstrated improvement in menstrual and nonmenstrual pain, dyspareunia and life quality postsurgery, but with recurrence rates of up to 54% and repetitive surgery risk, particularly in young women. The latest Cochrane meta-analysis assessed the efficacy of laparoscopic surgery in treatment of endometriosis-related pelvic pain, as studied in RCTs [27]. The analysis highlighted improved pain outcomes when compared with diagnostic future science group
Surgery versus pharmacological treatment for endometriosis –
laparoscopy alone, but no conclusions could be drawn in regard to severe endometriosis treatment or specific surgical interventions. Moreover, there were no published RCTs that compared effectiveness of surgery versus medical treatment for pain associated with endometriosis. A global consensus meeting held in 2011, in conjunction with the World Congress on Endometriosis in France, gathered opinions of 56 representatives and published a statement on the current management of endometriosis [28]. In regard to surgical management of endometriosis symptoms, it was agreed that appropriate surgical expertise and adequate technical resources were crucial aspects when planning surgery. It was stated that laparoscopic surgery should always be preferred over laparotomy, particularly in the case of severe endometriosis, and that excision, rather than ablation of endometriotic lesions, should be performed, although, superiority has not yet been proven in RCTs. There is some evidence that, in regard to deep dyspareunia, surgical treatment results in better outcomes and fewer side effects compared with medical treatment [29]. Women that underwent surgeries for excision of deep endometriotic lesions, including vaginal, rectal or sigmoid resection, experienced significant improvement in sexual functioning, quality of life and pelvic pain [30,31]. However, possible complications of extensive surgery must always be thoroughly discussed with the patient preoperatively. Surgical nerve interruption with laparoscopic uterine nerve ablation or laparoscopic presacral neurectomy, when combined with surgical treatment for endometriosis implants, have so far gained limited evidence supporting their use [32]. The addition of laparoscopic uterine nerve ablation displayed no additional benefit in pain relief while presacral neurectomy, although being found to have an overall difference in pain relief, might be specific for midline abdominal pain only and had significantly more adverse events. Treatment for infertility Pharmacological treatment
No evidence of fertility improvement was shown with the use of different ovulation suppression agents or the anti-inflammatory pentoxifylline, in subfertile women with endometriosis who were interested in pregnancy [33–35]. On the contrary, women with endometriosis who underwent IVF may benefit from prolonged GnRH agonists administration before treatment [36], as well as from oral contraceptive pills administration for 6–8 weeks prior to treatment future science group
perspective
with assisted reproductive technologies [37]. IVF outcomes in women with endometriosis seem, overall, similar to outcomes among patients with other indications when controlled for age [38], despite earlier reports of reduced pregnancy rates when compared with other indications [38,39]. Superovulation with or without intra uterine insemination increases pregnancy rates in women with mild endometriosis [40], while IVF should be suggested as first-line treatment for women with more severe disease, particularly those with compromised tubal function [28]. Surgery
A meta-analysis of randomized trials demonstrated an advantage of laparoscopic surgery compared with diagnostic laparoscopy in the treatment of subfertile women with minimal and mild endometriosis in regard to clinical pregnancy rates [41]. Conservative surgery was also suggested as effective for natural conception during the first year after the operation [42]. Surgery for more severe disease lacks conclusive support from randomized trials. Controversy exists in regard to the influence of endometriomas on fertility, the response to IVF treatments, and the possible diminished ovarian reserve following endometrioma resection. In women with unilateral, unoperated endometriomas undergoing IVF, no statistically significant difference was shown between the two ovaries in regard to the number of cysts, their dimension, the dose of gonadotrophins used or the number of oocytes retrieved [43]. Another study showed that, in the case of bilateral endometriomas at the time of IVF, the oocyte quality and the chances for pregnancy were not affected despite reduced responsiveness to ovarian hyperstimulation [44]. A Cochrane analysis summarized that there was no evidence for improved clinical pregnancy rates with surgery versus expectant management among women with endometriomas undergoing IVF [45]. A greater concern was raised in regard to the potential harm to the ovarian reserve with removal of endometriomas. A case–control, retrospective study analyzed 428 first-attempt IVF cycles in women with ovarian endometriosis compared with patients with tubal infertility and found no difference in IVF outcomes [46]. However, patients who underwent ovarian surgery prior to IVF treatment had significantly lower antral follicle count and required higher gonadotropin doses. Garcia-Velasco and Somigliana concluded that since the association between endometriomarelated injury and surgery-mediated damage still needs to be clarified, and since surgery is not
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perspective – Avraham & Seidman risk-free, surgery should be indicated only in the presence of large cysts, concomitant refractory pain or in the case that malignancy could not be ruled out [47]. This notion was further supported in a systematic review that showed surgery-related damage to ovarian reserve with declined serum antimullerian hormone, particularly in women operated for bilateral endometriomas [48]. A recent prospective study suggested that the presence of endometrioma per se was related to reduced ovarian reserve, as reflected by lower antimullerian hormone levels [49]. Serum antimullerian hormone levels were further reduced following endometrioma excision and the decline rate positively correlated with preoperative levels. Although the natural decline in ovarian reserve due to endometrioma compared with surgery-related decline should be further investigated, these results raise the need to carefully consider when to delay or avoid excision once fertility is desired. Combined therapy
A review of randomized trials that evaluated the effectiveness of hormonal suppression before or after surgery for endometriosis in relation to pain symptoms, recurrence rates and pregnancy rates, supported earlier assessments that found no benefit associated with postsurgical medical therapy and insufficient evidence of benefit from
presurgical therapy, with regard to the outcomes evaluated [50]. Conclusion
Endometriosis-related pain can be addressed with either medical therapy or surgery. Although not proven in RCTs, NSAIDs are widely prescribed. Different hormonal suppression agents are effective for pain control, but should be monitored for side effects and have high relapse rates when withdrawn. Newer effective solutions, such as dienogest and the levonorgestrel system, offer a better safety profile. Laparoscopic surgery for pelvic pain displays an alternative to medical treatment, but was not proven to be superior to it. In any case, surgery should be performed by experts in the field. Infertility related to endometriosis can be addressed with surgery in mild-to-moderate disease. The role of surgery for severe endo metriosis-related infertility has not yet been proven. The handling of endometriomas is under an ongoing debate. Future perspective
A better understanding of the pathophysio logy of endometriosis may launch a new generation of pharmacotherapy targeted at specific intracellular pathways and mechanisms.
Executive summary Endometriosis is a common disorder & the search for the ideal solution continues • Endometriosis is a chronic disorder with up to 50% prevalence in symptomatic women. The two main complications related to endometriosis are pain and infertility. • There are a lack of transparent clinical data in regard to treatment of endometriosis-related complications. Pelvic pain in endometriosis can be addressed with either pharmacotherapy or surgery • NSAIDs are widely used for the treatment of endometriosis-related pain, but were not proven to be effective over placebo in randomized controlled trials. • Hormonal suppression treatment is effective for pain palliation with no superiority of a specific agent, but might exhibit adverse side effects with prolonged use and high relapse rate with discontinuation. • Dienogest was proven to be effective for pain relief with improved safety profile. • Laparoscopic surgery improves pain outcomes, and should be performed by experts in the field with consensus agreement towards excision rather than ablation. Surgery is effective but limited in the treatment of endometriosis-related infertility & should be individualized • There is no evidence for medical treatment for fertility improvement. • IVF should be offered as first-line therapy for women with severe disease, with benefit from hormonal suppression prior to treatment. • In randomized controlled trials, surgery for subfertility proved to be effective only for mild disease. • Excision of endometriomas in women who desire future fertility did not demonstrate effectiveness and was even suggested as harmful in regard to ovarian reserve. • There is no benefit in pre- or post-surgical medical therapy for pain, recurrence rates and pregnancy rates. Conclusion • From the evident data from the literature to date, no single approach is ideal for all women. Individualization of therapy should be made according to the major complaint and must balance efficacy, safety and tolerability profiles. Future perspective • Ongoing research on the intracellular pathways involved in endometriosis pathophysiology holds promise for effective treatment with fewer adverse effects.
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Surgery versus pharmacological treatment for endometriosis –
New selective progesterone receptor modulator drugs seem, at present, to hold the most immediate promise to offer endometriosis patients an effective medical treatment with few side effects. Well-controlled randomized, prospective trials are needed comparing medical treatment versus surgery for endometriosis-related pain and assessing the impact of endomerioma excision for women with endometriosis who desire fertility. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
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Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. management of endometriosis. Expert Opin. Pharmacother. 14(3), 291–305 (2013).
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