Treatment Of Endometriosis-associated Pain Research Articles

9821 GnRH Analogues and Dienogest for Treatment of Endometriosis Associated Pain: A Systematic Review and Network Meta-Analysis

9821 GnRH Analogues and Dienogest for Treatment of Endometriosis Associated Pain: A Systematic Review and Network Meta-Analysis

Efficacy of acupuncture for endometriosis-associated pain: a multicenter randomized single-blind placebo-controlled trial

To evaluate the efficacy and safety of acupuncture in the treatment of endometriosis-associated pain. A multicenter, randomized, single-blind, placebo-controlled trial. Four tertiary hospitals in Jiangxi and Hainan Provinces. Women with endometriosis-associated pain aged between 20 and 40 years. Subjects were assigned randomly to receive either acupuncture or sham acupuncture treatment for 12 weeks, starting one week before each expected menstruation and administered as a 30-minute session once per day, 3 times a week. During the menstruation period, acupuncture was administered daily when pelvic pain associated with endometriosis occurred. After acupuncture or sham acupuncture treatment, the subjects were followed for another 12 weeks. Changes in maximum pain as assessed with the visual analog scale (VAS) for various pelvic pain, duration of dysmenorrhea, and scores on the Multidimensional Pain Inventory, Beck Depression Inventory, Profile of Mood States, and Endometriosis Health Profile from baseline to week 12 and week24. A total of 106 women were assigned randomly to the acupuncture and sham groups. In the acupuncture group, the reduction in the dysmenorrhea VAS score was significantly greater after treatment, but not at the end of the trial, compared to the sham group. The duration of pain was significantly shorter in the acupuncture group. All test scores were improved to a significantly greater extent in the acupuncture group than in the sham group at week 12 but not at week 24. Changes in nonmenstrual pelvic pain and dyspareunia VAS scores were not different between the groups. No severe adverse events or differences in adverse events were recorded. Acupuncture is an effective and safe method of relieving dysmenorrhea, shortening the pain duration, and improving wellbeing and quality of life in women with endometriosis-associated pain, although its efficacy fades after treatment is discontinued. NCT03125304.

Chinese Herbal Medicine, Alternative or Complementary, for Endometriosis-Associated Pain: A Meta-Analysis.

Current medical treatments for endometriosis-associated pain (EAP) have limitations, including symptom recurrence and hormonal side effects. For this reason, it is important to elucidate any alternative or complementary treatments available, while Chinese herbal medicine (CHM) shows potential to be this treatment. This study aims to provide evidence for the efficacy and safety of CHM for EAP. Randomized control trials comparing CHM to other treatments for EAP in women with endometriosis were considered eligible, and they were searched for in Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, as well as in the Chinese databases Sino-Med and CNKI, from inception to October 2021. Numerous outcomes were put through meta-analysis using a weighted mean difference and a 95% CI, and the results of dichotomous data were presented as a pooled RR with a 95% CI. A total of 34 eligible studies with 3389 participants were included. Compared with no treatment, there was a statistically significant pooled benefit of CHM on dysmenorrhea at the end of 3-month treatment, and these effects continued for 3 months, but not 9 months, after treatment. Compared with conventional therapy, a significant difference was found in the levels of pelvic pain with a lower rate of hot flush and irregular vaginal bleeding at the end of treatment for 3 months, but not after treatment. Comparing combined treatment with CHM and conventional therapy with conventional therapy alone, significant decreases were found in dysmenorrhea, dyspareunia, and pelvic pain after a 3-month treatment cycle, and in dysmenorrhea after a 4-month treatment cycle with a lower hot flash rate. In conclusion, CHM, used alone or in combination with conventional therapies, appears to have benefits in relieving EAP with fewer side effects than traditional treatment.

Systemic pharmacological verification of Guizhi Fuling decoction in treating endometriosis-associated pain

Ethnopharmacological relevanceGuizhi Fuling decoction (GZFL decoction) is a famous formula in the Synopsis of the Golden Chamber, which has a long history in treating endometriosis. However, its exact mechanism remains unclear. Aim of studyThis study aims to explore the mechanism of GZFL decoction in treating endometriosis, especially in alleviating endometriosis-associated pain. Materials and methodsA combination of system pharmacology and pharmacodynamics was used to explore the specific mechanism of GZFL decoction in the treatment of endometriosis-associated pain. First, the TCMSP database was used to search the components of the GZFL decoction; the parameter index was set as oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18, while the active ingredients of the drug were screened out. The disease targets of endometriosis were obtained from the TTD, OMIM, Genecards, and DisGeNET databases; the keyword was “endometriosis pain”. Network construction and analysis were performed using Cytoscape 3.7.2 software; the David database was used to enrich and analyze the pathways for alleviating endometriosis pain after GZFL decoction treatment. In addition, the network results were verified using experimental animal and cell research. ResultsThe results showed the following targets: 76 for the effective chemical components in the prescription, 1329 for disease pain, and 278 for the intersection of drugs and endometriosis pain. The enrichment results for these targets showed that the TNF-PI3K/Akt pathway exhibited research significance. In endometriosis rat models, the GZFL decoction reduced the volume of lesions and relieved pain symptoms. It also reduced the serum levels of IL-6, IL-1β, and TNF-α as well as their expression in the lesion tissues. The GZFL decoction also suppressed the activation of PI3K/Akt downstream signaling proteins. ConclusionsGZFL decoction could reduce the volume of lesions, suppress inflammation, and decrease the sensitivity to pain in endometriosis rat models through inhibiting PI3K/Akt pathway. This study provides a possible target for traditional Chinese medicine in treating endometriosis-associated pain.

O-305 SPIRIT long-term extension study: two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain

Abstract Study question To assess the long-term efficacy and safety of once-daily Relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain over two years. Summary answer Relugolix-CT previously demonstrated sustained improvement of endometriosis-associated pain and was generally well tolerated over 52 weeks. Research is ongoing: two-year results will be reported. What is known already SPIRIT 1&2 were international, Phase 3, replicate, randomized, double-blind, placebo-controlled studies of Relugolix-CT (relugolix 40mg, estradiol 1mg, norethisterone acetate 0.5mg) in premenopausal women with moderate-to-severe endometriosis-associated pain, which were followed by the open-label, 80-week, long-term extension. 52-week results showed sustained improvement in dysmenorrhea and non-menstrual pelvic pain (NMPP) with 84.8% and 73.3% of responders, respectively. Efficacy was evidenced by reductions in dysmenorrhea (82.8%,) NMPP (62.9%,) proportion of women using opioids, and improvements in function. Relugolix-CT was generally well tolerated. Bone mineral density (BMD) assessment showed minimal initial decline (<1%) from baseline followed by stabilization from Week 24 to 52. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1&2) were eligible to enroll in an 80-week open-label, single-arm, long-term extension study of safety and efficacy, representing up to 104 weeks of treatment in total. All women enrolled in the long-term extension study received once-daily oral Relugolix-CT. Analyses were performed based on the initial randomized treatment groups in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Participants/materials, setting, methods Primary endpoints are proportion of dysmenorrhea and NMPP responders at Weeks 52 and 104 based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable) and analgesic use. Responders are women who achieved a predefined, clinically meaningful reduction from baseline in NRS score and no increase in analgesic use. Secondary efficacy endpoints include change in Endometriosis Health Profile-30 pain domain scores, use of opioids/analgesics. Safety endpoints include adverse events and BMD (percent change). Main results and the role of chance Of 1251 randomized patients in SPIRIT 1&2, 1044 (83.4%) completed the pivotal studies; 802 (76.8%) enrolled in the long-term extension, and 681 (84.9%) completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the long-term extension population were consistent with those of the pivotal study population. The study remains ongoing at the time of writing. Efficacy and safety data with Relugolix-CT for up to Week 104, will be presented at the scientific session of the 2022 congress. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Wider implications of the findings Through 52 weeks of treatment, Relugolix-CT demonstrated sustained improvement of dysmenorrhea, NMPP, function, and reduced need for opiates in women with endometriosis-associated pain. No new safety concerns were identified, and treatment was associated with BMD loss <1%. Data from 104 weeks of treatment will be presented at the 2022 congress. Trial registration number NCT03654274

031 Medical and surgical management of endometriosis in teenagers

Menstrual symptoms such as dysmenorrhea are frequently reported, both in adults as in the adolescent population. A significant number of high school students report missed school days due to menstrual symptoms. Endometriosis is associated with painful menstruation and chronic pelvic pain. It’s true prevalence in the adolescent population is unknown, although 2/3rds of laparoscopies performed for pelvic pain in adolescents show endometriosis. Before discussing treatment, it is vital that severe menstrual pain is not regarded as normal, and should warrant further medical advice (which may include ultrasound) in case it has an impact on school and social activities, to reduce diagnostic and treatment delay. Treatment of endometriosis-associated pain may be medical and/or surgical, although data in the adolescent population are scarce. First line medical treatment can be offered with NSAIDs, and where appropriate hormonal treatment such as combined oral contraceptives or progestogens. Although GnRH-analogues have shown to be effective for pain treatment, they should be used very restrictively and with great caution due to their side effects and reduction of (peak) bone mineral density. Surgical treatment can be offered in case of pain not responding to hormonal treatment, or in case large cysts or bowel/ureter obstruction is found. Laparoscopy should be performed by an experienced team, to avoid repeat surgery and its associated risks. Postoperative hormonal treatment is advised to reduce recurrence rates.

Liriodendrin alleviates sciatic endometriosis-associated pain in rats via suppressing inflammatory response and regulating the signaling pathway of Pl3K/Akt/mToR

IntroductionLY294002 has been validated as a PI3K pan-inhibitor in the pathogenesis of airway inflammation, which attenuated IL-25-induced asthma-like AHR. Liriodendrin was proved to play essential roles in attenuating endometriosis-associated pain. This work aimed to gain a mechanical insight into the therapeutic efficiency of Liriodendrin administration on attenuating endometriosis-associated pain.Material and methodsVon Frey filament test and thermal hyperalgesia test were carried out to evaluate the acute and daily efficiency of drug administration. Western blot was used to analyze the expression of substance P, PI3K/AKT/mTOR, p-PI3K/p-AKT/p-mTOR, and CGRP. ELISA was performed to examine interleukin-1, interleukin-2, interleukin-6, TNF-α and PGE2 levels.ResultsAs a result, Liriodendrin significantly attenuated pain in endometriosis rats and restored the up-regulation of p-PI3K/p-AKT/p-mTOR in the endometriosis rats. The increased interleukin-1, interleukin-2, interleukin-6, TNF-α, and PGE2 levels were remarkably restored by Liriodendrin in endometriosis rats. Moreover, the activated expression of substance P in the ventral horn of the spinal cord of endometriosis rats was notably restored by Liriodendrin in addition to CGRP. Furthermore, Liriodendrin effectively restored the LPS induced up-regulation of p-PI3K/p-AKT/p-mTOR protein as well as the LPS activated IL-6, TNF-α, and IL-1β mRNA and protein expression in 12Z cells.ConclusionsWe found that compared with LY294200, Liriodendrin exerted a more evident therapeutic effect in the treatment of endometriosis-associated pain by suppressing the secretion of pro-inflammatory cytokines.

O-132 Sustained efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT 52-week data

Abstract Study question To assess the long-term (52-week) efficacy and safety of relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain. Summary answer Relugolix-CT demonstrated a sustained improvement of endometriosis-associated pain and maintenance of bone mineral density (BMD) over the extension treatment period. It was well tolerated. What is known already Endometriosis is a chronic condition characterized by symptoms of menstrual and non-menstrual pain, and dyspareunia, which have a substantial impact on women’s lives. SPIRIT 1 and 2 were Phase 3, randomized, double-blind, placebo-controlled studies of once-daily Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in premenopausal women (age 18–50 years) with surgically diagnosed endometriosis and moderate-to-severe dysmenorrhea and non-menstrual pelvic pain (NMPP) at baseline. These trials demonstrated a significant improvement of dysmenorrhea, NMPP and dyspareunia in women treated with Relugolix-CT, with a minimal decline in BMD vs placebo over 24 weeks. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials) were eligible to enroll in an open-label, single-arm, long-term safety and efficacy extension study for an additional 80 weeks. All women received once-daily oral Relugolix-CT. Analyses were done based on original randomization in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Here, 52-week efficacy and safety outcomes are presented. Participants/materials, setting, methods The primary endpoints were the proportion of dysmenorrhea and NMPP responders at Week 52, based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable). A responder was a woman who achieved a predefined, clinically meaningful reduction from baseline in NRS score with no increase in analgesic use. Secondary efficacy endpoints included change in Endometriosis Health Profile-30 (EHP-30) pain domain scores, and analgesic/opioid use. Safety endpoints included adverse events (AEs) and BMD evaluation. Main results and the role of chance Of 1261 randomized patients, 1044 completed the primary studies; 802 enrolled in the long-term extension and 681 completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the extension population were consistent with those of the original randomized population. Sustained improvement of endometriosis-associated pain was demonstrated with Relugolix-CT through 52 weeks, the proportion of responders for dysmenorrhea was 84.8% and 73.3% for NMPP. NRS least squares (LS) mean scores for dysmenorrhea and NMPP decreased from 7.4 (severe) and 6.0 (moderate) at SPIRIT study baseline to 1.3 (mild) and 2.2 (mild) at Week 52, equating to 82.8% and 62.9% reduction in dysmenorrhea and NMPP, respectively. Mean NRS for dyspareunia decreased from 5.9 (moderate) to 2.4 (mild), demonstrating 60.1% reduction with Relugolix-CT. Daily functioning measured by the EHP-30 pain domain score was improved (–38.1 point) and the majority of women (85.6%) were opioid-free at Week 52. There was no disproportionate increase in the incidence of AEs in the Relugolix-CT group with no new safety signals identified through the 52 weeks. BMD was preserved over the extension period with overall LS mean change from baseline to Week 52 of –0.83% (95% CI: –1.34, –0.32) for lumbar spine in the Relugolix-CT group. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 28 weeks of the extension period. Wider implications of the findings Relugolix-CT demonstrated a sustained improvement of dysmenorrhea, NMPP, and dyspareunia, and reduced pain-related functional limitations and the need for opioids over 52 weeks in women with moderate-to-severe endometriosis-associated pain. Relugolix-CT was generally well tolerated and associated with minimal BMD loss after treatment initiation followed by BMD maintenance over 52 weeks. Trial registration number NCT03654274

Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone–antagonist: a randomized clinical trial

To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP). A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial. Clinical centers. Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP. The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks. The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD). Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern. Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently. NCT02778399.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

BackgroundEndometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. MethodsWe performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix — 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) — as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesi...

A discrete choice experiment study of patient preferences regarding treatments for endometriosis-associated pain

A discrete choice experiment study of patient preferences regarding treatments for endometriosis-associated pain

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

BackgroundEndometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.MethodsWe performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix — 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) — as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.ResultsA total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.ConclusionsBoth higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670.)

Redox regulation of microRNAs in endometriosis-associated pain

Endometriosis is a chronic, painful condition with unknown etiology. A differential expression of microRNAs in the endometriotic tissues from women with endometriosis with pain compared to those without suggested a plausible role for miRNA or epigenetic mechanisms in the etiology of endometriotic pain. The peritoneal milieu is involved in maintenance of endometriotic lesion and nociception. We recently showed the mechanistic role for oxidized-lipoproteins (ox-LDLs) present in peritoneal fluid (PF) in endometriosis and pain. We explored the possibility of ox-LDLs modulating the expression of miRNAs in a manner similar to PF from women with endometriosis. Expression levels of miRNAs and their predicted nociceptive and inflammatory targets were determined in PF and ox-LDL treated human endometrial cell-lines. Samples from IRB-approved and consented patients with and without endometriosis or pain were used. These were compared to endometrial cell-lines treated with various forms of oxidized-lipoproteins. RNA (including miRNAs) were isolated from treated endometrial cells and expression levels were determined using commercial miRNome arrays. Cell lysates were used in immunoblotting for inflammatory proteins using a protein array. Twenty miRNAs including isoforms of miR-29, miR-181 and let-7 were mutually differentially expressed in cells treated with PF from endometriosis patients with pain and those treated with ox-LDL components. The ox-LDLs and endo-PF treatment also produced significant overexpression of microRNA predicted target genes nerve growth factor, interleukin-6 and prostaglandin E synthase and overexpression of their downstream protein targets Mip1α and MCP1. This study showed similarities between miRNA regulation in PF from endometriotic women and ox-LDLs present in abundance in the PF of these women. Key miRNAs responsible for targeting nociceptive and inflammatory molecules were downregulated in the presence of ox-LDLs and endo-PF, thus playing a role in the etiology of endometriotic pain. These redox-sensitive miRNAs can be of potential use as targets in the treatment of endometriosis-associated pain.

Selection of key recommendations for the management of women with endometriosis by an international panel of patients and professionals.

Can the differences in patients' and professionals' perspective regarding essential endometriosis care be accommodated in one set of key recommendations? Consensus between patients and professions on a key set of recommendations for essential endometriosis care was achieved. Guideline development alone will not lead to healthcare improvement. Quality indicators are needed to monitor actual care and guideline adherence. These can help with better implementation of the ESHRE guidelines in European hospitals and thereby improve the quality of endometriosis care. The first step in the development of quality indicators is to select a compact set of key recommendations. Using a RAND modified Delphi method, this study reports the systematic selection of key recommendations based on the ESHRE guideline 'Management of Women with Endometriosis' by an international expert panel of both patients and professionals during the study period of September 2015 and December 2015. An international panel of patients (n = 10) and medical professionals (n = 11) rated and prioritized the 83 recommendations extracted from the ESHRE guideline for relevance in three rounds. A strict consensus methodology was used to select key recommendations. The main outcome measure was one set of key recommendations for endometriosis care. A representative set of 17 key recommendations was selected from the preliminary set of 83 recommendations. This selection covers all dimensions of endometriosis care, including diagnosis, treatment of endometriosis-associated pain, treatment of endometriosis-associated infertility and miscellaneous topics such as prevention, menopause and relationship with cancer. Of the 21 experts, 17 participated in at least one round while 16 (76.2%) participated in all 3 rounds. The feasibility of the selected key recommendations was not assessed in this study. As not all panel members took part in all three rounds, some response bias may have occurred. This set of key recommendations is the first step in the development of quality indicators for monitoring and improving endometriosis care. The set is generic and can be used in hospitals internationally. A practice test should be conducted to assess the feasibility of our key recommendations in clinical practice. No funding was received for the conduct of this study. Members of the EndoKey study group did not receive payment. The authors and members of the EndoKey study group have no conflict of interest.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist: Results from a Phase 2, Randomized Controlled Study

Purpose Elagolix is a novel, oral GnRH antagonist that dose-dependently suppresses estradiol levels. This study evaluated safety and efficacy of elagolix vs. leuprorelin acetate (LA) and placebo in women with endometriosis-associated pain. Methods In this multicenter, double-blind study, women with laparoscopically confirmed endometriosis were randomized to oral elagolix 150 or 250 mg once daily, placebo or 3.75 mg LA intramuscularly (i.m.) monthly for 12 weeks. Placebo and LA patients were re-randomized to elagolix, and elagolix patients continued treatment for another 12 weeks. Results Baseline demographics were similar among groups (mean age 31.7 years). Significantly greater reductions in monthly mean pelvic pain compared with placebo (p&lt;0.05) were observed in both elagolix doses at week 4, elagolix 250 mg at week 8 and LA at weeks 4, 8 and 12. The mean (95% CI) percentage change in spinal bone mineral density (BMD) from baseline at week 12 was -1.05 (-1.68, -0.43), -0.80 (-1.53, -0.07) and -1.63 (-2.28, -0.99) for elagolix 150-mg, 250-mg and LA groups, respectively, compared with a mean percentage increase in placebo group (0.11 [-0.50, 0.71]). Headache was the most common adverse event for all treatment groups. Conclusions Both elagolix and LA reduced endometriosis-associated pain for up to 24 weeks of treatment and were associated with generally acceptable safety profiles in this study. Based on relatively small changes from baseline to week 12 in BMD, elagolix may offer a potential long-term treatment option for endometriosis-associated pain in affected women. Larger clinical studies with elagolix are warranted. Trial Registration Clinicaltrials.gov Identifier: NCT00797225.

Oxidation-sensitive nociception involved in endometriosis-associated pain.

Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2α, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.

Power over Pain: A Brief Review of Current and Novel Interventions for Endometriosis-Associated Pain

An estimated 10%-15% of women of reproductive age suffer from endometriosis and can be plagued with one or many forms of pain. It is no mystery that endometriosis is an extremely complex disease, with several factors leading to the predominant symptoms of infertility and pain. Although there are currently multiple options available for treating endometriosis-associated pain, none have the ability to completely relieve the symptoms. This review both highlights the current trends in treatment of endometriosis-associated pain and explores some novel options available for therapy directed towards oxidative stress, inflammation and nociceptive mechanisms of pain. A PubMed search was conducted to identify the most recent publications on the topic of pain associated with endometriosis, and further research was performed to clarify the mechanism by which current treatments target pain. Lastly, the authors include a review of pharmacological options at the forefront of endometriosis research. A more comprehensive understanding of the mechanisms behind endometriosis-associated pain will ultimately lead to more effective treatments and improved prognoses for patients.

ESHRE guideline: management of women with endometriosis

What is the optimal management of women with endometriosis based on the best available evidence in the literature? Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. NA. The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). NA.

Postoperative Depot Medroxyprogesterone Acetate versus Continuous Oral Contraceptive Pills in the Treatment of Endometriosis-Associated Pain: A Randomized Comparative Trial

Background/Aim: To evaluate the efficacy and tolerability of postoperative depot medroxyprogesterone acetate (DMPA) versus postoperative continuous oral contraceptive (OC) pills in the treatment of endometriosis-associated pain. Methods: After a conservative surgery, 84 patients with symptomatic endometriosis were randomized to receive either intramuscular DMPA (150 mg) every 12 weeks for 24 weeks or continuous OC pills (ethinyl estradiol 0.03 mg and gestodene 0.075 mg) daily for 24 weeks. At weeks 12 and 24 of the treatment phase, patients rated their satisfaction with treatment and reported pain improvement and adverse effects. Results: There was no significant difference in the percentages of patients who reported satisfaction between the DMPA group and the OC group at weeks 12 and 24 (92.9 vs. 90.5%, and 92.9 vs. 88.1%, respectively). The rates of withdrawal because of persistent pain or side effects in the two groups were similar. Pain scores improved significantly in both groups, but dysmenorrhea scores on a visual analog scale at week 24 were significantly higher in the OC group than in the DMPA group (p = 0.039). Conclusion: Both postoperative DMPA and postoperative OC pills for 24 weeks were found to be effective and acceptable options for treating endometriosis-associated pain.

Gonadotrophin-releasing hormone analogues and endometriosis: current strategies and new insights

Background: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5% to 10% of women in reproductive age and has been reported also in adolescents. Its main clinical presentations are chronic pelvic pain and infertility. Objective: To provide a comprehensive review of the recently published data concerning the mechanism of action of gonadotrophin-releasing hormone analogues (GnRHas) as well as to analyze their role in the management of endometriosis-associated pain and infertility in addition to its value in adolescent cases. Furthermore, to provide practical recommendations and new insights based on the best available information. Methods: Systematic search was performed of the Cochrane Library and Medical Literature Analysis and Retrieval System Online database looking for the different trials, reviews and various guidelines relating to GnRHas usage in the management of endometriosis-associated pain, infertility and in adolescent cases. Results: From a pathophysiological perspective, there is a growing scientific evidence that GnRHas exert its therapeutic effects by their classical pituitary downregulation and via a direct effect on the endometrial cells themselves. Accordingly, they represent an important medical option for the management of different aspects of this enigmatic disease. Conclusion: GnRHas have a valuable strategic role in treatment of endometriosis-associated pain and infertility as well as in adolescents above 16 years.