OBJECTIVE: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain. METHODS: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate. RESULTS: Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV=50.8%) and 78.1% at 200 mg twice daily (Elaris EM-IV=75.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.8% at 150 mg once daily (Elaris EM-IV=66.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV=67.2%). After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings. CONCLUSION: Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01760954 and NCT02143713.

This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg twice a day) versus subcutaneous depot medroxyprogesterone acetate (DMPA-SC) on bone mineral density (BMD), in women with endometriosis-associated pain (n = 252). All treatments induced minimal mean changes from baseline in BMD at week 24 (elagolix 150 mg: −0.11%/−0.47%, elagolix 75 mg: −1.29%/−1.2%, and DMPA-SC: 0.99%/−1.29% in the spine and total hip, respectively), with similar or less changes at week 48 (posttreatment). Elagolix was associated with improvements in endometriosis-associated pain, assessed with composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, including statistical noninferiority to DMPA-SC in dysmenorrhea and nonmenstrual pelvic pain components of the CPSSS. The most common adverse events (AEs) in elagolix groups were headache, nausea, and nasopharyngitis, whereas the most common AEs in the DMPA-SC group were headache, nausea, upper respiratory tract infection, and mood swings. This study showed that similar to DMPA-SC, elagolix treatment had minimal impact on BMD over a 24-week period and demonstrated similar efficacy on endometriosis-associated pain.

This Phase 2 study evaluated the safety and efficacy of elagolix for treating endometriosis-associated pain. A total of 155 women with laparoscopically confirmed endometriosis were randomized to placebo, elagolix 150 mg, or elagolix 250 mg once daily for 12 weeks. Placebo patients were rerandomized to elagolix and elagolix patients continued their dosing assignment for 12 additional weeks; the primary efficacy measure was changed from baseline in the monthly mean numerical rating scale for pain at week 12. Monthly mean (standard error of the mean) reductions were greater with elagolix versus placebo (−1.19 ± 0.18, −1.25 ± 0.18, and −0.88 ± 0.18 for elagolix 150 mg, 250 mg, and placebo, respectively); differences were not statistically significant. Monthly mean dysmenorrhea and nonmenstrual pelvic pain scores were reduced with elagolix, with significant differences for dysmenorrhea at weeks 8 and 12 versus placebo (P <.05). Minimal bone mineral density changes were observed with elagolix treatment. In women with endometriosis-associated pain, elagolix demonstrated an acceptable efficacy and safety profile in this Phase 2 study.

Objective The aim of this study was to estimate the efficacy of elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of endometriosis-associated pelvic pain. Methods This was a phase II, randomized, placebo-controlled parallel group study conducted at 37 US centers, consisting of an 8-week double-blind period followed by a 16-week open-label period. Patients were 137 women aged 18 to 49, with laparoscopically confirmed endometriosis and moderate to severe nonmenstrual pelvic pain and dysmenorrhea, who were administered elagolix 150 mg daily or placebo. The primary outcomes of the study were the daily assessment of dysmenorrhea, nonmenstrual pelvic pain and dyspareunia using a modified Biberoglu-Behrman scale. Results During the double-blind period, there were significantly greater mean reductions from baseline to week 8 in dysmenorrhea (-1.13 ± 0.11 vs. −0.37 ± 0.11, p<0.0001), nonmenstrual pelvic pain (-0.47 ± 0.07 vs. −0.19 ± 0.07, p = 0.0066), and dyspareunia scores (-0.61 ± 0.10 vs. −0.23 ± 0.10, p = 0.0070) in the elagolix group compared with placebo. Continued improvements were observed during the open-label treatment regardless of initial treatment allocation. Elagolix treatment was also associated with significant improvements in quality-of-life measures during the double-blind and open-label periods. The most common adverse events occurring with elagolix were nausea, headache and hot flush, each in 9.9% of patients. Conclusion Elagolix effectively reduced endometriosis-associated pelvic pain over a 24-week period and was well-tolerated.

BACKGROUNDThe technology for successful oocyte cryopreservation has evolved only over the past decade. Fewer than 300 pregnancies achieved with cryopreserved oocytes were reported as of the end of 2006. Two cryopreservation techniques are currently available: the slow-cooling method and vitrification. This article reviews the world literature on pregnancies conceived from cryopreserved oocytes and reports 3 such pregnancies conceived with a slow-cooling method in our facility.CASESThree patients who underwent in vitro fertilization/embryo transfer cycles had the supranumerary oocytes cryopreserved using a slow-cooling method. After a period of 2-7 months, the oocytes were thawed, fertilized and the resulting embryos were transferred. All 3 patients conceived and 2 delivered-1 singleton and 1 a set of twins. The third patient conceived twins and was in the third trimester of her pregnancy at this writing. Literature review indicates that the majority of pregnancies to date have been achieved with a slow-cooling protocol. However, recent advances in the vitrification technology have improved its effectiveness and because of its simplicity made it the method of choice in oocyte cryopreservation.CONCLUSIONBoth slow-freezing and vitrification methods for oocyte cryopreservation can be used effectively to achieve pregnancies. Vitrification is technically simpler and may be more effective than slow freezing.

BACKGROUNDThis study seeks to determine whether estrogen is able to regulate the expression of heparanase-1 (HPR1) in human endometrium.METHODSHPR1 expression and heparan sulphate (HS) deposition in the endometrium collected in various menstrual phases were analysed by immunohistochemical and immunofluorescence staining, respectively. HPR1 expression in the endometrial cells unexposed or exposed to estradiol was analysed by using RT-PCR and luciferase reporter assay. HPR1 activity was analysed by using a novel enzyme-linked immunosorbent assay (ELISA). Cell surface HS levels were analysed by flow cytometry. Serum HPR1 activity in women receiving follicle-stimulating hormone (FSH) for IVF was measured by ELISA.RESULTSHPR1 expression was rarely detected in the endometrium in the early and mid-proliferative phases but was increased in the late proliferative phase and in the secretory phases. HPR1 expression was negatively associated with HS in the basement membrane (BM) of the endometrial glands. HPR1 gene expression, HPR1 promoter activity and HPR1 enzymatic activity were increased in the endometrial cells when exposed to 17beta-estradiol (E(2)), whereas cell surface HS levels showed a decrease which could be blocked by PI-88, an HPR1 inhibitor. Serum HPR1 levels were increased in women with moderately elevated blood estrogen levels after receiving FSH.CONCLUSIONSHPR1 is differentially expressed in the endometrium in different menstrual phases. Estrogen plays an important role in inducing HPR1 expression, subsequently leading to HS degradation on the endometrial cell surface and in the BM of the endometrium.

Objective: To investigate the expression of heparanase-1, an endoglycosidase that degrades heparan sulfate proteoglycans, in eutopic and ectopic endometrial tissues from women with endometriosis.Design: An immunohistochemical study.Setting: Academic research laboratory and a private infertility clinic affiliated with a university medical center.Patient(s) Premenopausal women undergoing laparoscopy for endometriosis.Intervention(s): None.Main Outcome Measure(s):, Expression of heparanase-1 analyzed by immunohistochemical staining in 91 eutopic and 14 ectopic endometrial specimens.Result(s): We found that 17% (4/24) of the eutopic endometrial specimens in the early proliferative phase and 32% (9/28) of the samples in the midproliferative phase were heparanase-1 positive. However, >= 80% of eutopic endometrial specimens at late proliferate phase and at luteal phase were heparanase-1 positive. Twelve of 14 ectopic endometriotic specimens stained heparanase-1 positive. Comparison of heparanase-1 expression in paired eutopic and ectopic endometrial tissues revealed that 5 of 6 ectopic specimens in the early proliferative phase were heparanase-1 positive, whereas only I eutopic specimen was heparanase-1 positive. In comparison with our recent study of heparanase-1 expression in normal endometrium, we found that there was no significant difference in heparanase-1 I expression in the eutopic endometrium from women with or without endometriosis.Conclusion(s): Heparanase-1 was differentially expressed in the eutopic endometrium in the different menstrual phases. Heparanase-1 was highly expressed in the ectopic endometriotic lesions regardless of their menstrual phases, suggesting that the local environment is responsible for increased heparanase-1 expression.

Endometriosis is a benign gynecologic disorder characterized by the ectopic growth of misplaced endometrial cells. A unifying hypothesis to explain endometriosis has not been elucidated as yet but numerous investigations have implicated disturbances in the immune response as fundamental to its etiology and pathogenesis. Clearly, the immune system is involved in endometriosis. It is not clear, however, whether and to what extent this involvement is a primary response leading to the initiation, promotion, and progression of the disease or a secondary response to the ectopic endometrial growth in an attempt to restore homeostasis. Thus, although numerous studies have shown alterations in cell-mediated and humoral immunity in subjects with endometriosis, the importance of these changes remains obscure. This review considers the past two decades of investigation of immune function changes in women with endometriosis with the expectation that this information will ultimately provide the basis for developing new approaches to patient management.

OBJECTIVE:To quantitate antiapoptotic and proapoptotic gene expression in endometrial cells (ECs) of women with and without endometriosis.DESIGN:Determination of transcript abundance (TA) of apoptosis-regulating genes in eutopic and ectopic endometrial cells.SETTING:Institute for the Study and Treatment of Endometriosis, Chicago, Illinois, and university-based research laboratories.PATIENT(S):Women with (n = 10) and without (n = 6) endometriosis.INTERVENTION(S):None.MAIN OUTCOME MEASURE(S):Quantitative virtually multiplexed transcript abundance measurement (VMTA) of the BCL2, BCLxL, defender against cell death-1 (DAD-1), BCLxS, P53, Caspase-1, and proliferating cell nuclear antigen (PCNA) genes.RESULT(S):The TA ratio of antiapoptotic to proapoptotic isoforms of the BCL-X gene favors survival in eutopic and ectopic ECs from women with endometriosis, but not control ECs. This was found throughout the menstrual cycle for ectopic ECs. Eutopic but not ectopic ECs also expressed increased TA of the antiapoptotic DAD-1 gene in endometriosis. Eutopic and ectopic ECs from women with endometriosis expressed decreased TA of p53 and Caspase-1 compared to ECs from women without endometriosis. Expression of these genes was not correlated with the proliferative state of ECs based on TA of the PCNA gene.CONCLUSION(S):Dysregulation in expression of pro- and antiapoptotic regulatory genes characterizes eutopic and ectopic ECs from women with endometriosis. These results are consistent with apoptotic resistance and enhanced survival of ECs in endometriosis.

Purpose: To compare the effects of two different blastocyst thawing protocols on implantation, pregnancy, and live birth rates.Methods: Ninety four consecutive frozen-thawed blastocyst transfers from 1996 to 2002 were retrospectively analyzed. Blastocysts were cryopreserved using Menezo's two-step slow-freezing protocol. Frozen blastocysts were thawed for transfer according to Menezo's stepwise or two-step protocol. Immediately after thawing, assisted hatching was performed and all embryos were cultured for 3 to 5 h before transfer. Only viable embryos were selected for transfer.Results: Implantation, pregnancy ( determined by the presence of fetal cardiac activity), and live birth rates were significantly higher with two-step ( 25, 45.7, and 42.9%) than with stepwise thawing protocol (9.2, 18.6, and 16.9%, P < 0.01). The percentage of gestational sacs resulting in live babies was higher with two-step thawing ( 76.6%) than with stepwise thawing (50%, P = 0.04).Conclusions: We conclude that the two-step thawing protocol offers advantages over the stepwise method. The two-step thawing protocol dramatically increased embryo implantation potential, resulting in higher pregnancy rate, and subsequent live birth rate, after frozen blastocyst transfer.

Objective: To compare controlled ovarian hyperstimulation-intrauterine insemination (COH-IUI) or IVF-ET pregnancy rates per cycle (PR) and cycle and cumulative fecundity (f and cf) with COH-IUI or IVF-ET in endometriosis.Design: Retrospective analysis.Setting: Endometriosis research institute.Patient(s): Women with endometriosis and infertility (n = 313) who underwent consecutive COH-IUI (202 patients, 648 cycles), IVF-ET (111 patients, 139 cycles), or IVF-ET after failed COH-IUI (56 patients, 68 cycles).Intervention(s): None.Main Outcome Measure(s): Crude PR and life table-estimated f and cf.Result(s): With COH-IUI, 69 patients conceived 65 conceived with IVF-ET and 30 conceived with IVF-ET after COH-IUI (PR 11%, 47%, and 44%). With COH-IUI, six-cycle cf was 41%, and f for cycles 1-6 was 15%, 12%, 8%, 7%, 7%, and 0. With IVF-ET, three-cycle cf was 73%, whereas f for cycles 1-3 was 47%, 27%, and 33%. First-cycle f with IVF-ET was significantly higher than cf of six COH-IUI cycles. When die data were stratified according to the stage of endometriosis and women's age, the benefit of IVF over COH was even more pronounced. Prior COH-IUI failure did not adversely affect IVF-ET outcome.Conclusion(s): In endometriosis, PR, f, and cf are significantly higher with IVF-ET than COH-IUI, especially in stage IV and in women >38 years of age. Considering, adverse effects of prolonged ovarian stimulation on endometriosis, IVF-ET should be the first-line approach in the management of infertility in this disease. If COH-IUI is attempted, it should not exceed three to four cycles.

Small bowel involvement by endometriosis occurs in about 0.5% of patients, but nodular endometriosis involving the entire wall of the terminal ileum is extremely rare. Endometriotic nodules protruding into the intestinal lumen may lead to chronic, partial, or acute complete small bowel obstruction and associated clinical changes. If obstruction is partial, preoperative diagnosis is difficult and seldom suspected, and no reliable diagnostic tests are available. At laparoscopic surgery, performed typically for associated pelvic endometriosis, bowel lesions may easily be overlooked, especially in women with abdominal adhesions from earlier surgery. Surgical injury, tension tears, or postoperative edema may contribute in such cases to the development of acute, complete small bowel obstruction, which may be difficult to differentiate from postoperative ileus. The patient may deteriorate rapidly and develop abdominal sepsis and multiple organ failure with high risk of mortality. Because of increased production of tumor necrosis factor-alpha by autologous monocytes, endometriosis may predispose to development of severe sepsis and septic shock. (J Am Assoc Gynecol Laparosc 8(1):161-166, 2001)

Objective: To determine the duration of time to the recurrence of pain attributable to endometriosis after the discontinuation of treatment with danazol or a GnRH agonist (GnRH-a) in patients who have had a satisfactory response to the treatment.Design: Retrospective study.Setting: Nine academic medical centers in three countries.Patient(s): Three hundred twenty-seven women with diagnosed and staged endometriosis who were treated with at least 6 months of danazol or a GnRH-a and who experienced significant pain relief with therapy.Intervention(s): None.Main Outcome Measure(s): Duration of pain relief after completion of treatment as determined by a patient-initiated report of pain recurrence or increase in pain severity requiring intervention.Result(s): The median time to the recurrence of pain was 6.1 months for patients treated with danazol and 5.2 months for patients treated with a GnRH-a.Conclusion(s): Although there was a lack of uniformity in treatment effects across sites, the analyses have taken into account major covariant effects. The time to the recurrence of endometriosis-associated pain after danazol treatment was slightly longer than that after GnRH-a treatment. (Fertil Steril(R) 0;70:293-6. (C)1998 by American Society for Reproductive Medicine.).

In an article in this issue of the journal, Bergendal et al. report lower rates of fertilization in women with endometriosis than in controls with tubal factor infertility.The authors further indicate that other parameters of the in vitro fertilization (IVF) cycle were unaffected by the disease, the quality of the embryos in both groups was comparable, and with the same number

The aim of this study was to evaluate objectively whether or not discontinuous albumin gradients enrich the proportion of Y-bearing human sperm. A blinded, collaborative trial design was employed whereby a licensed centre prepared the sperm fractions using licensed procedures, coded the sperm slides and then sent them to an independent laboratory for determination of the X:Y ratio in each sperm fraction using X and Y chromosome-specific probes and double label fluorescence in-situ hybridization (FISH). The identification codes and FISH results were collated by an independent third observer. Two albumin gradient methods which are currently used by licensed centres for male sex pre-selection, protocol 3 and modified protocol 3, were tested. Essentially the same results were obtained for the two methods. Highly motile sperm fractions were recovered from the albumin gradients, and the recoveries of motile spermatozoa (1.3-8.5%) were within the optimal range reported to produce maximal enrichment of Y-bearing spermatozoa. FISH analysis, however, revealed no enrichment for Y-bearing spermatozoa with either method, and the overall X:Y ratios were not significantly different from 1.0. Some samples showed marginal enrichment of Y-bearing spermaotozoa, whereas others showed marginal enrichment of X-bearing spermaotozoa. In conclusion, this collaborative study has demonstrated that the protocol 3 and modified protocol 3 albumin gradient procedures do not enrich Y-bearing spermatozoa. The clinical use of albumin gradients for male sex preselection should be reconsidered in the light of this and other evidence.

Objective: To compare demographic, epidemiologic, and medical data and to evaluate diagnostic trends in women with endometriosis and chronic pelvic pain symptoms or endometriosis and infertility.Design: Retrospective analysis.Setting: Institute for the Study and Treatment of Endometriosis.Patient(s): Six hundred ninety-three consecutive patients with endometriosis and chronic pelvic pain (n = 357) or endometriosis and infertility (n = 336).Intervention(s): None.Main Outcome Measure(s): Demographic and epidemiologic parameters, diagnostic trends.Result(s): Women with pelvic symptoms were younger, had less formal education, more frequent family history, and higher frequency and intensity of pelvic complaints. Mean ages at first symptom and diagnosis were lower in the pain group, but stage of endometriosis at first diagnosis was more advanced. The mean ''diagnostic delay'' was longer in the pelvic pain than in the infertile group (6.35 versus 3.13 years), but it decreased during three consecutive 5-year intervals in both groups, and there was also a gradual decrease in the frequency of advanced endometriosis at; the time of first diagnosis.Conclusion(s): Demographic and epidemiologic parameters in women with endometriosis differ, depending whether chronic pelvic pain or infertility are the presenting symptoms. In the pain group, diagnostic delay is longer and endometriosis at diagnostic laparoscopy more advanced, indicating progressiveness of the disease. During the last 15 years, diagnostic delay steadily of clined.

Purpose: The purpose of this study was to evaluate the clinical effectiveness of subcutaneous estradiol pellets in donor oocyte recipients with an inadequate endometrial response.

Objective: To report an unusual case of embryo implantation and superfetation.Design: Retrospective case analysis.Setting: Oak Brook Fertility Center.Patient(s): A 41-year-old woman underwent two consecutive ovarian stimulation cycles interrupted by a normal menstrual period. Ovulation and implantation occurred during both cycles. The first embryo conceived developed normally until term; the second failed to develop.Intervention(s): None.Main Outcome Measure(s): Retrospective analysis of stored blood samples for serum E-2, P, and beta-hCG levels.Result(s): Rising beta-hCG levels during menstruation indicated normal embryonic implantation in the absence of adequate E-2 and P support, During subsequent ovarian stimulation, there was a normal follicular and E-2 response and normal ovulation in spite of the ongoing pregnancy. The second embryo, conceived during the second cycle of stimulation, implanted but failed to develop.Conclusion(s): This unusual case indicates that E-2, P, and endometrial thickness requirements for successful implantation may not always be as critical as postulated previously. The absence of a decidual response might have facilitated superfetation. (C) 1997 by American Society for Reproductive Medicine.