Efficacy and safety of different subsequent therapies after fertility preserving surgery for endometriosis: A systematic review and network meta-analysis.

BACKGROUND: Endometriosis (EMT) is a benign and common estrogen-dependent disease. Hormonal therapy improves pain symptoms in most women with EMT. However, in many cases, laparoscopic fertility preservation surgery is considered a common treatment for EMT. The present study aimed to evaluate the efficacy and safety of dienogest, leuprolide, danazol, gestrinone, mifepristone and levonorgestrel intrauterine system (LNG-IUS) in relieving symptoms and delaying the recurrence of EMT cysts after fertility protection surgery. METHODS: We searched PubMed, the Cochrane Library, Web of Science, EMBase, China National Knowledge Infrastructure, VIP Database, China Biology Medicine disc, WanFang Data databases to collect randomized controlled trials (RCT) related to dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS as a follow-up treatment after fertility preserving surgery for EMT. After literature screening, data extraction and quality evaluation, effective rate, recurrence rate, pregnancy rate and adverse reaction rate were used as outcome indicators to evaluate the efficacy and safety of drugs. Evidence networks included in the study were drawn and publication bias was assessed. The drugs most likely to be the best postoperative treatment were explored through mixed comparison of different drugs and efficacy ranking. RESULT: Effective rate: dienogest, leprerelin, gestrinone and LNG-IUS were better than placebo after EMT fertility preservation surgery; dienogest was superior to mifepristone and danazol. LNG-IUS is superior to danazol. LNG-IUS has the highest potential for improving the effectiveness of EMT symptoms. Recurrence rate: the application of dienogest, leuprolide, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was lower than that of placebo; dienogest and LNG-IUS were lower than danazol. The recurrence rate of dinorgestrel was the last place with the highest performance. Pregnancy rate: in the cases with fertility requirements, dienogest and,leuprolide were better than placebo after EMT fertility preservation surgery; dienogest was superior to danazol, gestrinone and mifepristone. Leuprolide is superior to danazol and gestrinone. The first rank of dienogest pregnancy rate was the highest. Adverse reaction rate: the application of dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was higher than that of placebo. After placebo, LNG-IUS had the highest adverse reaction rate. CONCLUSION: For patients after fertility preserving surgery for EMT, the recurrence rate of dienogest was the last place with highest preference. The first rank of dienogest pregnancy was the highest.

[Mechanism of Shaofu Zhuyu Decoction in treatment of endometriosis-associated dysmenorrhea with syndrome of cold coagulation and blood stasis based on MSK1/2].

This study aims to decipher the mechanism underlying the effect of Shaofu Zhuyu Decoction on endometriosis(EMT)-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis based on mitogen-and stress-activated protein kinase 1/2(MSK1/2).We employed a random number table to randomly assign SPF female non-pregnant rats into the sham group, and treated the rest rats with autologous transplantation+refrigerator freezing for the modeling of the syndrome of cold coagulation and blood stasis.The modeled rats were then randomly assigned into the control group and high-, medium-and low-dose Shaofu Zhuyu Decoction groups.The rats in the low-, medium-, and high-dose decoction groups were respectively administrated with 9, 4.5, and 2.3 g·kg~(-1) decoction through gavage once a day for 2 consecutive weeks, and those in the control group were administrated with 0.24 mg·kg~(-1) gestrinone through gavage once every 3 days for 2 weeks.After that, the size of ectopic focus in each rat was measured via laparotomy.Enzyme-linked immunosorbent assay(ELISA) was adopted to determine the expression of interleukin(IL)-6, IL-10, prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α).Western blot was employed to determine the protein levels of MSK1/2 and dual-specificity phosphatase 1(DUSP1) and real-time quantitative polymerase chain reaction(RT-PCR) to determine the mRNA levels of the two genes in rat eutopic endometrial tissue.Compared with the sham group, the model group showed increased levels of IL-6, PGE2, and TNF-α while decrease level of IL-10 in the serum(P<0.01).Compared with the model group, the high-and medium-dose decoction groups and the gestrinone group had declined levels of IL-6, PGE2, and TNF-α while risen level of IL-10 in the serum(P<0.01).The model group had lower protein levels and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the sham group(P<0.01). The high-and medium-dose decoction groups and the gestrinone group had higher protein and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the model group(P<0.01).The results indicated that Shaofu Zhuyu Decoction can regulate the abnormal expression of pro-inflammatory cytokines TNF-α, IL-6, and PGE2 and anti-inflammatory cytokines IL-10 and DUSP1 via MSK1/2 to alleviate EMT-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis.

Combinatory effects of current regimens and Guizhi Fuling Wan on the development of endometriosis.

OBJECTIVE: Endometriosis, defined as the growth of endometrial glands and stromal cells in a heterotopic location under the cyclic influence of ovarian hormones, is a common gynecological disorder manifested by chronic pelvic pain and infertility. In traditional Chinese medicine, endometriosis is characterized by stagnation of vital energy (qi) and blood stasis. Guizhi Fuling Wan (GFW) was first described in Chinese canonical medicine to treat disorders associated with stagnation of qi and blood stasis, including endometriosis. Therefore, the current study aimed to test the effects of combining GFW with western medicine on the suppression of endometriosis. MATERIALS AND METHODS: Endometriosis was generated by suturing endometrial tissue on the peritoneal wall of C57BL/6JNarl mice. The mice were subsequently treated with either GFW or current hormonal therapies or in combination for 28 days. RESULTS: Endometriosis development was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone or GFW + medroxyprogesterone acetate (MPA). The expression of intercellular adhesion molecule 1 (ICAM-1) was inhibited by GFW, Gestrinone, MPA, Visanne, GFW + Gestrinone, GFW + MPA and GFW + Visanne. Vascular endothelial growth factor (VEGF) expression was inhibited by GFW, Gestrinone, Visanne, GFW + Gestrinone and GFW + MPA. Both ICAM-1- and VEGF-reducing effects of GFW were attenuated by western medicines. Administration of GFW, MPA, Visanne, GFW + MPA and GFW + Visanne also correspondingly reduced macrophage population in peritoneal fluid. GFW, MPA, Visanne, GFW + MPA and GFW + Visanne enhanced B-cell population in peritoneal fluid. CONCLUSION: The current study reveals the therapeutic effects of GFW on endometriosis. However, the combination of GFW and current hormonal therapies potentially impedes the efficacy of each individual agent in treating endometriosis.

Repurposing gestrinone for tumor suppressor through P21 reduction regulated by JNK in gynecological cancer.

Endometriosis has been shown to increase the risk of gynecological cancers. However, the effect of gestrinone, a clinical endometriosis drug, on gynecological cancers remains unclear. This study aimed to understand the effect of gestrinone on gynecological cancers. A retrospective study was conducted using the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database (NHIRD) to observe the risk of gynecological cancers. Medication records from the Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital CSMUH and cancer records from the Taiwan Cancer Registry were collected to analyze the correlation between gestrinone use and gynecological cancers. Subsequently, human cell lines were used to investigate the effect of gestrinone on gynecological cancers. A total of 8330 endometriosis patients were enrolled, and analyses revealed that endometriosis patients had a higher risk of developing ovarian and endometrial cancer. However, the rate of cervical cancer was not statistically different (P = 0.249). Analyses of both the NHIRD and CSMUH databases revealed that gestrinone may reduce the risk of gynecological cancer. Cellular experiments verified the anticancer effects of gestrinone, which effectively and specifically inhibited the growth of HeLa cervical cancer cells, decreased P21 expression via JNK phosphorylation, and induced apoptosis. Combining the results of clinical database analysis and cell experiments, our findings prove that gestrinone has the potential to protect against cancer through regulation of the JNK-P21 axis. Repurposing the anticancer efficacy of gestrinone may be a strategy for targeted therapy in the future.

Clinical comparison of mifepristone and gestrinone for laparoscopic endometriosis.

Endometriosis is a common disease among women of childbearing age, and it is the main cause of dysmenorrhea and infertility. This article analyzes the efficacy of mifepristone and gestrinone in the treatment of endometriosis. The results showed that the recurrence rate of mifepristone group and gestrinone group were 8.33% and 5%, respectively, which was significantly lower than 23.33% of the control group. Before and after treatment, LH, endocrine test results FSH PRL had no obvious change in mifepristone group and gestrinone group, while E2 decreased, as mifepristone group (141.7±31.2) pmol/L, gestrinone group (64.2±11.7) pmol/L. The incidence of adverse reactions and liver dysfunction in the mifepristone group were significantly lower than those the gestrinone group (P<0.05). Mifepristone and gestrinone can be used for endometriosis postoperative adjuvant treatment, is safe and effective, but using mifepristone has the lower rate of adverse reaction. In conclusion, mifepristone is a current research focus, its mechanism of action in the process of exploration, has broad prospects in the treatment of endometriosis, its long-term application security is paid more and more attention.

Progesterone receptor modulators for endometriosis.

BACKGROUND: Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen primarily during the reproductive years. Owing to their antiproliferative effects in the endometrium, progesterone receptor modulators (PRMs) have been advocated for treatment of endometriosis. OBJECTIVES: To assess the effectiveness and safety of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis. SEARCH METHODS: We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to 28 November 2016. We handsearched reference lists of articles retrieved by the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by the Cochrane Collaboration. Primary outcomes included measures of pain and side effects. MAIN RESULTS: We included 10 randomised controlled trials (RCTs) with 960 women. Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, one RCT compared asoprisnil versus placebo, one compared ulipristal versus leuprolide acetate, and four compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogues, or a different dose of gestrinone. The quality of evidence ranged from high to very low. The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide confidence intervals), and indirectness (outcome assessed in a select subgroup of participants). Mifepristone versus placebo One study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.At three months, the mifepristone group had lower rates of dysmenorrhoea (odds ratio (OR) 0.08, 95% confidence interval (CI) 0.04 to 0.17; one RCT, n =352; moderate-quality evidence), suggesting that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95% CI 0.11 to 0.51; one RCT, n = 223; low-quality evidence). However, the mifepristone group had higher rates of side effects: Nearly 90% had amenorrhoea and 24% had hot flushes, although the placebo group reported only one event of each (1%) (high-quality evidence). Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Mifepristone dose comparisons Two studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present. However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5 mg dose may be less effective than 5 mg or 10 mg for treating dysmenorrhoea or dyspareunia. Gestrinone comparisons Ons study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95% CI 0.33 to 1.56; two RCTs, n = 230; very low-quality evidence), dysmenorrhoea (OR 0.72, 95% CI 0.39 to 1.33; two RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95% CI 0.37 to 1.86; two RCTs, n = 222; very low-quality evidence). The gestrinone group had a higher rate of hirsutism (OR 2.63, 95% CI 1.60 to 4.32; two RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95% CI 0.38 to 0.98; two RCTs, n = 302; low-quality evidence). Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95% CI 0.50 to 1.26; two RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95% CI 0.90 to 2.33; two RCTs, n = 302; low-quality evidence).When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhoea score was higher in the gestrinone group (MD 0.35 points, 95% CI 0.12 to 0.58; one RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95% CI 0.62 to 0.04; low-quality evidence). The gestrinone group had lower rates of amenorrhoea (OR 0.04, 95% CI 0.01 to 0.38; one RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95% CI 0.06 to 0.63; one study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95% CI 2.64 to 198.66; one RCT, n = 49; low-quality evidence).Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present. Asoprisnil versus placebo One study (n = 130) made this comparison but did not report data suitable for analysis. Ulipristal versus leuprolide acetate One study (n = 38) made this comparison but did not report data suitable for analysis. AUTHORS' CONCLUSIONS: Among women with endometriosis, moderate-quality evidence shows that mifepristone relieves dysmenorrhoea, and low-quality evidence suggests that this agent relieves dyspareunia, although amenorrhoea and hot flushes are common side effects. Data on dosage were inconclusive, although they suggest that the 2.5 mg dose of mifepristone may be less effective than higher doses. We found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.

Effect of mifepristone in the different treatments of endometriosis.

OBJECTIVE: To observe the effect of small-dose mifepristone conservative treatment and laparoscopic combined with mifepristone in the treatment of endometriosis. MATERIALS AND METHODS: Sixty-five endometriosis cases were given small-dose mifepristone conservative treatment and were assessed for the effect of this treatment; 92 cases were randomly divided into control group (taking gestrinone) and observation group (mifepristone), FSH, P, PRL and E2 levels were compared before and after treatment, and pregnancy investigation and each sex hormone level monitoring were followed-up at one year after drug withdrawal. RESULTS: Using mifepristone, FSH, P, E2, and LH levels all significantly changed six months after treatment and recovered 12 months after drug withdrawal; when comparing the pelvic symptoms, endometrial thickness showed that mifepristone was significantly effective (p < 0.01), and the pregnancy rate was 27.69%. Comparing the two groups, none of the total effective rate, pregnancy rate one year of follow-up, and recurrence rates were significantly different; hormone levels in the both groups were significantly decreased or increased (p < 0.05) after treatment. The two groups had no significant difference (p > 0.05), but 12 months after drug withdrawal, in the control group (not in the observation group), LH level was still significantly different (p < 0.05) compared pre-treatment. CONCLUSIONS: In the conservative treatment, mifepristone can safely improve the hormone levels, reduce the thickness of the endometrium, alleviate symptoms. With laparoscopic minimally invasive combined drug therapy, mifepristone has a significant effect, with a more followed-up pregnancy rate, less recurrence, and no drug accumulation side-effects, hence it is worthy of clinical application.

Role of Medical Management for Uterine Leiomyomas.

Uterine leiomyomas, or fibroids, are the most common benign tumor in reproductive aged women. Affected women may remain asymptomatic or may report symptoms related to abnormal uterine bleeding, infertility, or pelvic pain and pressure. Depending on a patient's symptomatology and reproductive plans, treatment options include expectant management, medical management (hormonal and non-hormonal), or surgical management (myomectomy or hysterectomy). In those wishing to defer surgical management, non-hormonal therapies such as non-steroidal anti-inflammatory drugs and tranexamic acid have been shown to decrease menstrual blood loss. In patients with more symptomatic leiomyomas, hormonal therapies such as gonadotropin-releasing hormone agonists and selective progesterone receptor modulators are effective at reducing leiomyoma volume, uterine size, and menstrual blood loss. This manuscript will detail the available and emerging hormonal and non-hormonal treatments for symptomatic uterine leiomyomas.

[Effect of Tripterygium wilfordii glycosides combined with gestrinone on endometriosis and serum cytokine expression].

To study the effect of Tripterygium wilfordii glycosides and gestrinone on endometriosis and serum cytokine expression, 135 cases of endometriosis patients were divided into treatment group(n=69) and control group(n=68). The observation group was orally given with T. wilfordii glycosides, 20 mg, tid, for 4 weeks. Then, the dose decreased to 10 mg/time, tid. T. wilfordii glycosides combined with gestrinone capsule(2.5 mg) were given in the 1st and 4th day of a menstrual cycle. Later, the administration was fixed at two times every week. The course of treatment lasted for 3 months. The control group was treated with gestrinone capsule(according to the same intake method). The serum-related cytokine levels before and after treatment were determined, and the clinical efficacy was observed. The results showed the total effective rate of the observation group was 89.71%, which was obviously higher than that of the control group(74.63%), with statistically significant differences(P<0.05). After treatment, TDS showed varying degrees of decreases, with a better effect in the observation group (P<0.01). Before treatment, serum TGF-ß, IL-10 and IL-4 level had no significant difference. After treatment, all of these cytokines decreased, particularly for the observation decreased(P<0.01). Before and after treatment, serum IL-17 had no obvious difference between the two groups. This study suggested that the integrated traditional Chinese medicine and western medicine has an obvious clinical efficiency in endometriosis. Its mechanism may be related to the effective regulation of cytokines.

Gestrinone combined with ultrasound-guided aspiration and ethanol injection for treatment of chocolate cyst of ovary.

AIM: The aim of this study was to determine clinical performance of gestrinone combined with ultrasound-guided aspiration and ethanol injection in treating chocolate cyst of ovary. METHODS: Sixty-eight patients enrolled in this study were randomly divided into two groups: control group and combination treatment group. In the control group, 34 patients were treated with ultrasound-guided aspiration and ethanol injection. In the combination treatment group, 34 patients received gestrinone p.o. following ultrasound-guided aspiration and ethanol injection. RESULTS: The recurrence rate of chocolate cyst was 10-fold lower in the combination treatment group (2.94%, 1/34) than in the control group (29.4%, 10/34) at 12 months. The effective rate for reduction of chocolate cyst was significantly higher in the combination treatment group (94.12%, 32/34) than in the control group (64.71%, 22/34) (P = 0.009). CONCLUSION: Gestrinone combined with ultrasound-guided aspiration and ethanol injection therapy is an effective treatment for ovarian chocolate cyst with low recurrence rate.

[Clinicopathological features of 151 cases with abdominal wall endometriosis].

OBJECTIVE: To investigate clinicopathological features of abdominal wall endometriosis (AWE). METHODS: A retrospective study was conducted on 151 consecutive AWE patients undergoing treatment in Affiliated Obstetrics and Gynecology Hospital, Fudan University from January 2003 to December 2010. The period of following up was at range of 16 to 97 months. RESULTS: (1) The incidence of AWE was 1.96% (166/8469). All 151 AWE cases followed up had previous cesarean sections. The period between the previous cesarean section (CS) and the onset of symptoms of AWE was 24 months (3 - 192 months). However, the latency was not associated with the age at CS, incision site, gestational week at CS, duration of lactation, postpartum menstruation recovery, the choice of contraceptives and size of AWE (P > 0.05). The duration of disease, defined to be the time interval between the onset of symptoms and surgery, was 26 months (2 - 168 months), which was negatively correlated with the latent period (r = -0.267, P < 0.05) and was positively with size of AWE (patients with large-scar endometrioma with diameter of lesions ≥ 3 cm had longer disease duration than those with small-scar endometriomas < 3 cm, r = 0.326, P < 0.05). (2) The rate of pre-operational ultrasonography detection was 97.4% (147/151). The lesion size detected by pre-operative ultrasonography was significantly smaller than that measured intraoperatively by palpation (20 mm versus 35 mm, P < 0.05). Moreover, only 26.5% (40/151) of AWE patients were found to have deep infiltration by pre-operative ultrasonography. (3) All patients were managed by surgical treatment to completely excise lesions on the abdominal wall. Of all 34 patients (22.5%, 34/151) took medicine pre-operatively while 57 patients (37.7%, 57/151) taking medicine post-operatively. The rate of recurrence was 3.1% (3/96) of cases with lesions ≥ 3 cm, which was significantly lower than 17.8% (8/45) in cases with lesion < 3 cm (P < 0.05). (4) After surgery, the symptoms were found to be relieved in 93.4% (141/151) of patients. The recurrence rate was 7.8% (11/141) while the average recurrent time was (20 ± 16) months. CONCLUSION: Surgery is the main management on AWE. The risk factors associated with recurrence were size of lesion and postoperative medication.

Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK.

The study was to investigate the effect of gestrinone on the growth of human uterine leiomyoma cells and on the levels and activity of p38, Src and estrogen receptor alpha (ERα). Human uterine leiomyoma cells were cultured and treated with dimethylsulfoxide (DMSO) or a gestrinone concentration gradient. Morphological changes were observed and apoptosis was evaluated. Levels of p38 and phosphorylated-p38 (pp38) were assayed by enzyme-linked immunosorbent assay (ELISA). Levels of ERα and Src were analyzed using real-time RT-PCR and Western blotting. The result showed that gestrinone significantly inhibited the growth of cultured human uterine leiomyoma cells in a concentration- and time-dependent manner, with a 50% inhibitory concentration (IC(50)) value and corresponding 95% confidence intervals (CI) of 43.67 (23.46∼81.32), 27.78 (12.51∼61.68) and 15.25 (7.17∼32.43) µmol/L at 20, 40 and 60h, respectively. Compared with control-treated leiomyoma cells, gestrinone significantly reduced both the expression of ERα (P<0.05) and the levels of phospho-Ser167-ERα (P<0.05). Gestrinone also markedly suppressed the level of phospho-Tyr416-Src (P<0.05). Moreover, gestrinone significantly increased the ratio of phospho-p38/p38 mitogen-activated protein kinase (MAPK) (P<0.05). However, no significant increase in apoptosis or cell cycle arrest was observed (P>0.05) in response to the tested concentrations of 0.1 to 3.0µmol/L. As a conclusion, gestrinone suppresses the proliferation of uterine leiomyoma cells mainly by regulating the activity of ERα/Src/p38 MAPK in a concentration-dependent manner at a low concentration of 0.1∼3.0µM, but not significantly regulating apoptosis. Gestrinone opposes the growth of uterine leiomyoma through multiple genes.

Chinese herbal medicine for endometriosis.

BACKGROUND: Endometriosis is characterized by the presence of tissue that is morphologically and biologically similar to normal endometrium in locations outside the uterus. Surgical and hormonal treatment of endometriosis have unpleasant side effects and high rates of relapse. In China, treatment of endometriosis using Chinese herbal medicine (CHM) is routine and considerable research into the role of CHM in alleviating pain, promoting fertility, and preventing relapse has taken place.This review is an update of a previous review published in the Cochrane Database of Systematic Reviews 2009, issue No 3. OBJECTIVES: To review the effectiveness and safety of CHM in alleviating endometriosis-related pain and infertility. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) and the following English language electronic databases (from their inception to 31/10/2011): MEDLINE, EMBASE, AMED, CINAHL, and NLH.We also searched Chinese language electronic databases: Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Sci & Tech Journals (VIP), Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and Chinese Medical Current Contents (CMCC). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving CHM versus placebo, biomedical treatment, another CHM intervention; or CHM plus biomedical treatment versus biomedical treatment were selected. Only trials with confirmed randomisation procedures and laparoscopic diagnosis of endometriosis were included. DATA COLLECTION AND ANALYSIS: Risk of bias assessment, and data extraction and analysis were performed independently by three review authors. Data were combined for meta-analysis using relative risk (RR) for dichotomous data. A fixed-effect statistical model was used, where appropriate. Data not suitable for meta-analysis were presented as descriptive data. MAIN RESULTS: Two Chinese RCTs involving 158 women were included in this review. Both these trials described adequate methodology. Neither trial compared CHM with placebo treatment.There was no evidence of a significant difference in rates of symptomatic relief between CHM and gestrinone administered subsequent to laparoscopic surgery (95.65% versus 93.87%; risk ratio (RR) 1.02, 95% confidence interval (CI) 0.93 to 1.12, one RCT). The intention-to-treat analysis also showed no significant difference between the groups (RR 1.04, 95% CI 0.91 to 1.18). There was no significant difference between the CHM and gestrinone groups with regard to the total pregnancy rate (69.6% versus 59.1%; RR 1.18, 95% CI 0.87 to 1.59, one RCT).CHM administered orally and then in conjunction with a herbal enema resulted in a greater proportion of women obtaining symptomatic relief than with danazol (RR 5.06, 95% CI 1.28 to 20.05; RR 5.63, 95% CI 1.47 to 21.54, respectively). Overall, 100% of women in all the groups showed some improvement in their symptoms.Oral plus enema administration of CHM showed a greater reduction in average dysmenorrhoea pain scores than did danazol (mean difference (MD) -2.90, 95% CI -4.55 to -1.25; P < 0.01). Combined oral and enema administration of CHM also showed a greater improvement measured as the disappearance or shrinkage of adnexal masses than with danazol (RR 1.70, 95% CI 1.04 to 2.78). For lumbosacral pain, rectal discomfort, or vaginal nodules tenderness, there was no significant difference between CHM and danazol. AUTHORS' CONCLUSIONS: Post-surgical administration of CHM may have comparable benefits to gestrinone but with fewer side effects. Oral CHM may have a better overall treatment effect than danazol; it may be more effective in relieving dysmenorrhoea and shrinking adnexal masses when used in conjunction with a CHM enema. However, more rigorous research is required to accurately assess the potential role of CHM in treating endometriosis.

Progestagens and anti-progestagens for pain associated with endometriosis.

BACKGROUND: Endometriosis is a chronic inflammatory condition defined by the presence of glands and stroma outside the uterine cavity. It occurs in 7% to 10% of all women of reproductive age and may present as pain or infertility. The pelvic pain may be in the form of dysmenorrhoea, dyspareunia or pelvic pain. Initially a combination of estrogens and progestagens was used to create a pseudopregnancy and alleviate the symptoms associated with endometriosis. Progestagens alone or anti-progestagens have been considered as alternatives because they are inexpensive and may have a better side effect profile than other choices. OBJECTIVES: To determine the effectiveness of both the progestagens and anti-progestagens in the treatment of painful symptoms ascribed to the diagnosis of endometriosis. SEARCH METHODS: We used the search strategy of the Menstrual Disorders and Subfertility Group to identify all publications which described or might have described randomised controlled trials (RCTs) of any progestagen or any anti-progestagen in the treatment of symptomatic endometriosis. We updated the review in 2011. SELECTION CRITERIA: We considered only RCTs which compared the use of progestagens and anti-progestagens with other interventions, placebo or no treatment for the alleviation of symptomatic endometriosis. DATA COLLECTION AND ANALYSIS: We have added six new studies, bringing the total of included studies to 13 in the update of this review. The six newly included studies evaluated progestagens (comparisons with placebo, danazol, oral or subdermal contraceptive, oral contraceptive pill and danazol, gonadotrophin-releasing hormone (GnRH) analogue and other drugs). The remaining studies compared the anti-progestagen gestrinone with danazol, GnRH analogues or itself. MAIN RESULTS: The progestagen medroxyprogesterone acetate (100 mg daily) appeared to be more effective at reducing all symptoms up to 12 months of follow-up (MD -0.70, 95% CI -8.61 to -5.39; P < 0.00001) compared with placebo. There was evidence of significantly more cases of acne (six versus one) and oedema (11 versus one) in the medroxyprogesterone acetate group compared with placebo. There was no evidence of a difference in objective efficacy between dydrogesterone and placebo.There was no evidence of a benefit with depot administration of progestagens versus other treatments (low dose oral contraceptive or leuprolide acetate) for reduced symptoms. The depot progestagen group experienced significantly more adverse effects.There was no overall evidence of a benefit of oral progestagens over other medical treatment at six months of follow-up for self-reported efficacy. Amenorrhoea and bleeding were more frequently reported in the progestagen group compared with other treatment groups.There was no evidence of a benefit of anti-progestagens (gestrinone) compared with danazol. GnRH analogue (leuprorelin) was found to significantly improve dysmenorrhoea compared with gestrinone (MD 0.82, 95% CI 0.15 to 1.49; P = 0.02) although it was also associated with increased hot flushes (OR 0.20, 95% CI 0.06 to -0.63; P = 0.006). AUTHORS' CONCLUSIONS: There is only limited evidence to support the use of progestagens and anti-progestagens for pain associated with endometriosis.

Chinese herbal medicine for endometriosis.

BACKGROUND: Endometriosis is characterized by the presence of tissue that is morphologically and biologically similar to normal endometrium in locations outside the uterus. Surgical and hormonal treatment of endometriosis have unpleasant side effects and high rates of relapse. In China, treatment of endometriosis using Chinese herbal medicine (CHM) is routine and considerable research into the role of CHM in alleviating pain, promoting fertility, and preventing relapse has taken place. OBJECTIVES: To review the effectiveness and safety of CHM in alleviating endometriosis-related pain and infertility. SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) and the following English language electronic databases (from their inception to the present): MEDLINE, EMBASE, AMED, CINAHL, NLH on the 30/04/09.We also searched Chinese language electronic databases: Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Sci & Tech Journals (VIP), Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and Chinese Medical Current Contents (CMCC). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving CHM versus placebo, biomedical treatment, another CHM intervention, or CHM plus biomedical treatment versus biomedical treatment were selected. Only trials with confirmed randomisation procedures and laparoscopic diagnosis of endometriosis were included. DATA COLLECTION AND ANALYSIS: Risk of bias assessment, and data extraction and analysis were performed independently by three review authors. Data were combined for meta-analysis using relative risk (RR) for dichotomous data. A fixed-effect statistical model was used, where appropriate. Data not suitable for meta-analysis are presented as descriptive data. MAIN RESULTS: Two Chinese RCTs involving 158 women were included in this review. Both these trials described adequate methodology. Neither trial compared CHM with placebo treatment.There was no evidence of a significant difference in rates of symptomatic relief between CHM and gestrinone administered subsequent to laparoscopic surgery (95.65% versus 93.87%; risk ratio (RR) 1.02, 95% confidence interval (CI) 0.93 to 1.12, one RCT). The intention-to-treat analysis also showed no significant difference between the groups (RR 1.04, 95% CI 0.91 to 1.18). There was no significant difference between the CHM and gestrinone groups with regard to the total pregnancy rate (69.6% versus 59.1%; RR 1.18, 95% CI 0.87 to 1.59, one RCT).CHM administered orally and then in conjunction with a herbal enema resulted in a greater proportion of women obtaining symptomatic relief than with danazol (RR 5.06, 95% CI 1.28 to 20.05; RR 5.63, 95% CI 1.47 to 21.54, respectively).Overall, 100% of women in all the groups showed some improvement in their symptoms.Oral plus enema administration of CHM showed a greater reduction in average dysmenorrhoea pain scores than did danazol (mean difference (MD) -2.90, 95% CI -4.55 to -1.25; P < 0.01).Combined oral and enema administration of CHM showed a greater improvement, measured as the disappearance or shrinkage of adnexal masses, than with danazol (RR 1.70, 95% CI 1.04 to 2.78). For lumbosacral pain, rectal discomfort, or vaginal nodules tenderness, there was no significant difference either between CHM and danazol. AUTHORS' CONCLUSIONS: Post-surgical administration of CHM may have comparable benefits to gestrinone but with fewer side effects. Oral CHM may have a better overall treatment effect than danazol; it may be more effective in relieving dysmenorrhea and shrinking adnexal masses when used in conjunction with a CHM enema. However, more rigorous research is required to accurately assess the potential role of CHM in treating endometriosis.

Endometriosis: current therapies and new pharmacological developments.

Endometriosis is a chronic inflammatory condition that is responsive to management with steroids. The establishment of a steady hormonal environment and inhibition of ovulation can temporarily suppress ectopic implants and reduce inflammation as well as associated pain symptoms. In terms of pharmacological management, the currently available agents are not curative, and treatment often needs to be continued for years or until pregnancy is desired. Similar efficacy has been observed from the various therapies that have been investigated for endometriosis. Accordingly, combined oral contraceptives and progestins, based on their favourable safety profile, tolerability and cost, should be considered as first-line options, as an alternative to surgery and for post-operative adjuvant use. In situations where progestins and oral contraceptives prove ineffective, are poorly tolerated or are contraindicated, gonadotrophin-releasing hormone analogues, danazol or gestrinone may be used. Future therapeutic options for managing endometriosis must compare favourably against existing agents before they can be considered for inclusion into current practice. Finally, as reproductive prognosis is not ameliorated by medical treatment, it is not indicated for women seeking conception.

Treatment of pelvic pain associated with endometriosis.

Pain associated with endometriosis requires careful evaluation to exclude other potential causes and may involve a number of different mechanisms. Both medical and surgical treatments for pain related to endometriosis are effective and choice of treatment must be individualized.

Does gestrinone antagonize the effects of estrogen on endometrial implants upon the peritoneum of rats?

OBJECTIVE: To evaluate the effects of estrogen treatment in combination with gestrinone on an experimental rat model of endometriosis. METHODS: Uterine transplants were attached to the peritoneum of female Wistar rats via a surgical autotransplantation technique. The implanted area was measured during the proestrus phase and after hormonal treatment. We performed morphometric analysis and examined the macroscopic and morphometric alterations of endometrial implants after hormonal treatment in ovariectomized rats. RESULTS: The high dose of estrogen caused macroscopic increases in the endometrial implant group compared with other groups, which were similar to increases in the proestrus phase. The low dose showed morphometric development of implants, such as an increase in number of endometrial glands, leukocyte infiltration and mitosis. Gestrinone antagonized both doses of estrogen. CONCLUSION: Our findings suggest that gestrinone antagonizes estrogen's effects on rat peritoneal endometrial implants.