Real-World Characterization of Women with Diagnosed Endometriosis Initiating Therapy with Elagolix Using a US Claims Database.

PURPOSE: Elagolix is an oral gonadotropin-releasing hormone antagonist approved in the United States for the management of moderate to severe pain associated with endometriosis. We performed a real-world evaluation of the demographic and clinical characteristics of women diagnosed with endometriosis who were initiating elagolix therapy in the United States. PATIENTS AND METHODS: This retrospective cohort database analysis included women 18-49 years of age with ≥1 pharmacy claim for elagolix between August 2018 and December 2019 from the Copyright © 2020 Truven Health Analytics LLC. All Rights Reserved. Women had continuous medical and pharmacy health plan enrollment during the baseline period (year immediately preceding the index date [date of earliest elagolix claim]) and had ≥1 medical claim with endometriosis (International Classification of Diseases [ICD]-9/10 code [617.x and N80.x]) on or before the index date. Baseline demographics, comorbidities, ICD code-based endometriosis anatomic site, endometriosis-related treatments, and pain symptoms were summarized descriptively. RESULTS: The study included 2083 patients with mean age at baseline of 33.2 ± 8.1 years. Comorbidities most commonly recorded were non-cancer, non-endometriosis pain (59.5%), including arthritis/joint pain (43.7%) and back/neck pain (31.7%), and mental disorder (40.7%), including anxiety (32.7%). The majority of endometriosis diagnosis codes recorded referred to unspecified location (52.3%) and pelvic peritoneum (23.0%); 61.0% of patients received a medical endometriosis-related treatment in the baseline period, with the most common treatments being contraceptives (various routes of administration, 40.2%) and progestins (31.7%). Additionally, 35.4% of the patients received an endometriosis-related surgery during baseline, with the most common being laparoscopy (33.2% of all patients). Opioids were used during the baseline period by 57.3% of the patients. For pain symptoms, 71.5%, 30.4%, and 19.3% of the patients had claims for pelvic pain, dysmenorrhea, and dyspareunia, respectively. CONCLUSION: Endometriosis therapies were used by a significant proportion of patients with endometriosis in the year immediately preceding elagolix initiation.

Achieving clinically meaningful response in endometriosis pain symptoms is associated with improvements in health-related quality of life and work productivity: analysis of 2 phase III clinical trials.

BACKGROUND: Endometriosis-related pain symptoms have a negative impact on health-related quality of life and productivity. In fact, as endometriosis-related symptom severity and the number of symptoms experienced increases, health-related quality of life decreases. Dysmenorrhea and nonmenstrual pelvic pain are prominent symptoms experienced by women with endometriosis and were shown to have improved with the oral, nonpeptide gonadotropin-releasing hormone antagonist, elagolix. OBJECTIVE: The objective of this post hoc analysis was to address the question of if patients show a clinical response (in dysmenorrhea or nonmenstrual pelvic pain), do they also have improvements in health-related quality of life and in productivity? STUDY DESIGN: This post hoc analysis used data from the Elaris Endometriosis-I and Elaris Endometriosis-II phase III, randomized, placebo-controlled studies. A surgical diagnosis of endometriosis (in the past 10 years), premenopausal, aged 18-49 years, and moderate to severe endometriosis-associated pain were among the inclusion criteria for both trials. Women self-reported pain daily using a scale ranging from 0 (no pain) to 3 (severe pain); daily pain was assigned to either dysmenorrhea or nonmenstrual pelvic pain based on self-reported bleeding on that particular day. In addition, their self-reported endometriosis-associated pain must have been an average of moderate or severe during the month leading to baseline for inclusion in the trial program. Patients were characterized as achieving a clinical response for dysmenorrhea or nonmenstrual pelvic pain (ie, responder or nonresponder), which was defined as women who did not have an increase in analgesic use and who met the pain reduction score threshold at month 3. Pain reduction score thresholds were defined separately for dysmenorrhea and nonmenstrual pelvic pain in the trial using receiver-operating characteristics analysis. Health-related quality of life was assessed using the Endometriosis Health Profile-30; work productivity was assessed using the Health-Related Productivity Questionnaire. RESULTS: Women enrolled in Elaris Endometriosis-I (n = 871) and Elaris Endometriosis-II (n = 815) were included in this analysis. Patients with a clinical response during treatment to dysmenorrhea or nonmenstrual pelvic pain also experienced a meaningful improvement in all domains of the Endometriosis Health Profile-30 at month 3. Patients who did not show a dysmenorrhea or nonmenstrual pelvic pain clinical response at month 3 did not exhibit mean improvements in Endometriosis Health Profile-30 domain scores that indicate an Endometriosis Health Profile-30 responder. Productivity improved among dysmenorrhea clinical responders. In the Elaris Endometriosis-I study, clinical responders lost a total of 5.9 hours compared with a total of 13.0 hours for nonresponders of employment-related work at month 3 (P < .0001). Among women in the Elaris Endometriosis-II study, a total of 4.1 hours and 10.4 employment-related hours were lost at month 3 for dysmenorrhea responders vs nonresponders (P < .001). Similar results were obtained when analyzed by non-enstrual pelvic pain responder status. CONCLUSION: Women with moderate to severe endometriosis-related pain, who are clinical responders based on dysmenorrhea and nonmenstrual pelvic pain, also experience significant and clinically meaningful improvement in health-related quality of life and productivity as measured by the Endometriosis Health Profile-30 and Health-Related Productivity Questionnaire, respectively.

Health Care Utilization and Costs Associated with Endometriosis Among Women with Medicaid Insurance.

BACKGROUND: Endometriosis is a painful chronic inflammatory disease caused by endometrial tissue implanting and growing outside the uterus, resulting in pelvic pain symptoms and subfertility. Treatment imposes a substantial economic burden on the patient and health care system. OBJECTIVE: To evaluate direct health care utilization and costs among women newly diagnosed with endometriosis compared with age-matched controls in a U.S. Medicaid population. METHODS: This retrospective cohort study used deidentified health care claims from the 2007-2015 MarketScan Multi-State Medicaid Database. Women (aged 18-49 years) newly diagnosed with endometriosis (ICD-9-CM 617.xx) during January 2008 through September 2014 were identified (date of first diagnosis = index date). Age-matched women without endometriosis (controls) were selected from the database and assigned index dates matching the distribution for endometriosis patients. Direct health care resource utilization (HCRU) and costs (medical and pharmacy) over the 12-month post-index period (2015 U.S. dollars) were computed by service category (hospitalization, emergency room visits, outpatient services, and prescriptions) and compared between study cohorts using the chi-square test for proportions and t-test for continuous variables. RESULTS: The final sample included 15,615 endometriosis patients and 86,829 matched controls. HCRU during the 12-month post-index follow-up period was significantly higher for endometriosis cases compared with controls in all measured categories. Hospital admissions occurred among 33.1% of cases and 7.2% of controls, and 65.8% of endometriosis patients were admitted for endometriosis-related surgery. Emergency room visits occurred in 71.5% of cases, and 42.2% of controls. Mean (SD) office visits were 10.4 (8.5) for endometriosis patients and 5.1 (6.9) for controls. Endometriosis patients had significantly more prescription claims than controls, 45.9 (42.0) versus 25.1 (39.1). Mean total direct health care costs were $13,670 ($29,843) for cases versus $5,779 ($23,614) for controls. All differences between cases and controls were significant at P < 0.001. CONCLUSIONS: Health care costs and resource utilization in all measured categories were higher among endometriosis cases than controls. The economic burden of endometriosis among patients with Medicaid insurance is substantial, underscoring the unmet medical need for earlier diagnosis and cost-effective treatments. DISCLOSURES: This study was funded by AbbVie and conducted by Truven Health Analytics, an IBM Company. AbbVie participated in developing the study design, data analysis and interpretation, manuscript writing and revisions, and approval for publication. Soliman and Vora are employees of AbbVie and may own AbbVie stock/stock options. Surrey has served in a consulting role on research to AbbVie and is on the speaker bureau for Ferring Laboratories. Bonafede and Nelson are employees of Truven Health Analytics, an IBM Company, which received compensation from AbbVie for the overall conduct of the study and preparation of the manuscript. Agarwal has served in a consulting role on research to AbbVie. Preliminary results of this study were previously presented in a podium session at the 2017 American Society for Reproductive Medicine Scientific Congress and Expo; October 28-November 1, 2017; San Antonio, TX.

Impact of elagolix treatment on fatigue experienced by women with moderate to severe pain associated with endometriosis.

OBJECTIVE: To evaluate the efficacy of elagolix, an oral GnRH antagonist, for the reduction of fatigue in women with moderate or severe endometriosis-associated pain. DESIGN: Randomized, double-blind, multicenter, placebo-controlled phase III trial. SETTING: Clinics. PATIENT(S): A total of 860 women treated with elagolix or placebo. INTERVENTION(S): Women received either elagolix at 150 mg daily (QD) orally, elagolix at 200 mg twice daily (BID) orally, or placebo. MAIN OUTCOME MEASURE(S): Change from baseline to month 1, 3, and 6 visits, in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a questionnaire T-scores. RESULTS(S): At baseline, 54%-74% of women with moderate to severe pain associated with endometriosis reported having fatigue-related issues "quite a bit" or "very much," depending on the question asked. Fatigue extent was reduced to 29%-43% and 14%-29% for women treated with elagolix at 150 mg QD and 200 mg BID, respectively, at 6 months, compared with 35%-50% with placebo. The resultant decrease in fatigue T-scores was significant after elagolix treatment compared with placebo at 6 months, with changes of -2.21 and -5.90 with elagolix at 150 mg QD and 200 mg BID, respectively. Significant reduction in fatigue scores were observed among patients reporting clinically meaningful response "reduction" in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (-7.31, -6.62, and -4.31, respectively) compared with nonresponders. CONCLUSION(S): In women with moderate to severe endometriosis related pain, elagolix significantly reduces fatigue levels.

Reintervention Rates After Myomectomy, Endometrial Ablation, and Uterine Artery Embolization for Patients with Uterine Fibroids.

BACKGROUND: Women with uterine fibroids (UF) may undergo less invasive procedures than hysterectomy, including myomectomy, endometrial ablation (EA), and uterine artery embolization (UAE); however, long-term need for reintervention is not well characterized. We estimated reintervention rates for 5 years and identified predictors of reintervention. MATERIALS AND METHODS: A longitudinal retrospective cohort study was conducted in women in MarketScan® Commercial Claims and Encounters (Truven Health Analytics) aged 18-49 years with UF diagnosis before myomectomy, EA, or UAE from 2008 to 2014. Patients were categorized by initial procedure (index date) and required to have ≥12 months of continuous coverage before and after. Kaplan-Meier analyses and Cox proportional hazard models were used to estimate survival without reintervention and hazard of reintervention for 5 years. RESULTS: The study included 35,631 women with myomectomy (n = 13,804: 8,018 abdominal, 941 hysteroscopic, and 4,845 laparoscopic), EA (n = 17,198), and UAE (n = 4,629). Myomectomy had the lowest 12-month reintervention rate (4.2%), followed by UAE (7.0%), then EA (12.4%; both p < 0.001 relative of myomectomy). Estimates of 5-year reintervention rates were 19% for myomectomy (17%, 28%, and 20% for abdominal, hysteroscopic, and laparoscopic, respectively), 33% for EA, and 24% for UAE. EA and UAE had adjusted hazard ratios of 2.63 (95% confidence interval [CI], 2.44-2.83) and 1.56 (95% CI, 1.42-1.72). Prior anemia, bleeding, pelvic inflammatory disease, and abdominal and pelvic pain increased the hazard of reintervention. CONCLUSION: Reintervention rate estimates ranged from 17% to 33% for 5 years after myomectomy, EA, and UAE for patients with UF. Risk of requiring reintervention should be considered during treatment selection.

Risk of Developing Comorbidities Among Women with Endometriosis: A Retrospective Matched Cohort Study.

BACKGROUND: Endometriosis has been associated with higher rates of various chronic conditions, but its epidemiological data are fragmented and dated. We sought to compare the incidence of developing commonly occurring comorbidities among patients with and without endometriosis in a large, contemporary patient cohort that reflects real-world clinical practice. MATERIALS AND METHODS: A cohort of women aged 18-49 with incident endometriosis was extracted from the 2006-2015 de-identified Clinformatics® DataMart commercial insurance claims database (OptumInsight, Eden Prairie, MN). Endometriosis was identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 617.x on ≥1 inpatient or emergency department claim or ≥2 outpatient claims. Nonendometriosis control patients were exactly matched 4:1 to cases based on state, insurance plan type, and age (±1 year). Based on a literature review and expert consultation, 22 comorbidities were identified for analysis. The risk of developing a comorbidity post-index date was analyzed with stratified Cox proportional hazards models. RESULTS: There were 26,961 cases and 107,844 controls. Mean age was 36 years. The adjusted risk of developing a comorbid condition among endometriosis cases was statistically significantly higher than the matched controls for all 22 comorbidities (p ≤ 0.001) and was at least twice as large for nine comorbidities (infertility/subfertility, ovarian cyst, uterine fibroids, pelvic inflammatory disorder, interstitial cystitis, irritable bowel syndrome, constipation/dyschezia, ovarian cancer, and endometrial cancer). CONCLUSION: The incidence of developing many comorbidities was significantly higher among endometriosis patients compared with matched women without endometriosis. Additional research is needed to establish the implications for healthcare resource use.

Arcuate uterus: is there an impact on in vitro fertilization outcomes after euploid embryo transfer?

OBJECTIVE: To study the impact of the arcuate uterus on euploid blastocyst-stage embryo transfer outcomes after comprehensive chromosomal screening (CCS). DESIGN: Controlled retrospective trial. SETTING: Tertiary care assisted reproduction technology (ART) center. PATIENT(S): Consecutive patients undergoing in vitro fertilization and euploid embryo transfer after CCS during 2014. INTERVENTION(S): Ultrasound examinations and office hysteroscopy; array comparative genomic hybridization to perform CCS after a trophectoderm biopsy. MAIN OUTCOME MEASURE(S): Implantation and live-birth rates. RESULT(S): Patients were divided into two groups based on the presence (group 1) or absence (group 2) of arcuate uterus. Exclusion criteria were donor oocytes, evidence of other endometrial cavitary abnormalities, prior uterine surgery, and arcuate uterus <4 mm. Group 1 included 78 patients with arcuate uterus of mean depth 5.43 ± 1.81 mm (range: 4-9.5 mm) undergoing 83 transfer cycles. Group 2 included 354 controls undergoing 378 transfer cycles. There were no differences between the groups in baseline characteristics or mean number of euploid embryos transferred. Cycle outcomes were similar between the two groups: rates of implantation (63.7% vs. 65.4%), live birth (68.67% vs. 67.81%), biochemical pregnancy (8.4% vs. 7.65%), and spontaneous abortion (4.8% vs. 4.27%). CONCLUSION(S): Arcuate uterus has no impact on ART outcomes after euploid embryo transfer subsequent to CCS, so arcuate uterus should be considered an incidental finding without an indication for surgical resection.

Changes in Healthcare Spending After Diagnosis of Comorbidities Among Endometriosis Patients: A Difference-in-Differences Analysis.

INTRODUCTION: We sought to characterize changes in healthcare spending associated with the onset of 22 endometriosis-related comorbidities. METHODS: Women aged 18-49 years with endometriosis (N = 180,278) were extracted from 2006-2015 de-identified Clinformatics® DataMart claims data. For 22 comorbidities, comorbidity patients were identified on the basis of having a first comorbidity diagnosis after their initial endometriosis diagnosis. Controls were identified on the basis of having no comorbidity diagnosis and were matched 1:1 to comorbidity patients on demographics and baseline spending. Total medical and pharmacy spending was measured during 12 months before and after each patient's index date (first comorbidity diagnosis for comorbidity patients, and equal number of days after earliest endometriosis claim for controls). Pre-post spending differences were compared using difference-in-differences linear regression. Total and comorbidity-related cumulative spending per patient for all endometriosis patients were calculated annually for the 5 years following endometriosis diagnosis. RESULTS: The number of endometriosis patients with each comorbidity varied between 121 for endometrial cancer and 16,177 for fatigue. Healthcare spending increased significantly with the onset of eight comorbidities: breast cancer, ovarian cancer, pregnancy complications, systemic lupus erythematosus/rheumatoid arthritis/Sjogren's/multiple sclerosis, infertility, uterine fibroids, ovarian cyst, and headache [p < 0.001 except for headache (p = 0.045)]. Spending decreased significantly for fatigue, cystitis/UTI, and eczema [p < 0.001 except for fatigue (p = 0.048)] and was not statistically different for the other 11 comorbidities. Difference-in-differences estimates were significantly higher for comorbidity patients for all comorbidities except eczema (p ≤ 0.003). Mean 5-year total cumulative spending was $58,191 per endometriosis patient, of which between 11% and 23% was attributable to comorbidity-related medical claims. CONCLUSION: For all but one of the 22 comorbidities associated with endometriosis, comorbidity onset was associated with a relative increase in total healthcare spending. FUNDING: AbbVie Inc.

Treatment Patterns, Complications, and Health Care Utilization Among Endometriosis Patients Undergoing a Laparoscopy or a Hysterectomy: A Retrospective Claims Analysis.

INTRODUCTION: Hysterectomy and laparoscopy are common surgical procedures used for the treatment of endometriosis. This study compares outcomes for women who received either procedure within the first year post initial surgery. METHODS: The study used data from the Truven Health MarketScan claims databases from 2004 to 2013 to identify women aged 18-49 years who received an endometriosis-related laparoscopy or hysterectomy. Patients were excluded if they did not have continuous insurance coverage from 1 year before through 1 year after their endometriosis-related procedure, if they were diagnosed with uterine fibroids prior to or on the date of surgery (i.e., index date), or if they had a hysterectomy prior to the index date. The descriptive analyses examined differences between patients with an endometriosis-related laparoscopy or hysterectomy in regard to medications prescribed, complications, and hospitalizations during the immediate year post procedure. RESULTS: The final sample consisted of 24,915 women who underwent a hysterectomy and 37,308 who underwent a laparoscopy. Results revealed significant differences between the cohorts, with women who received a laparoscopy more likely to be prescribed a GnRH agonist, progestin, danazol, or an opioid analgesic in the immediate year post procedure compared to women who underwent a hysterectomy. In contrast, women who underwent a hysterectomy generally had higher complication rates. Index hospitalization rates and length of stay (LOS) were higher for women who had a hysterectomy, while post-index hospitalization rates and LOS were higher for women who had a laparoscopy. For both cohorts, post-procedure complications were associated with significantly higher hospitalization rates and longer LOS. CONCLUSION: This study indicated significantly different 1-year post-surgical outcomes for patients who underwent an endometriosis-related hysterectomy relative to a laparoscopy. Furthermore, the endometriosis patients in this analysis had a considerable risk of surgical complications, subsequent surgeries, and hospital admissions, both during and after their initial therapeutic laparoscopy or hysterectomy. FUNDING: AbbVie.

GnRH agonist administration prior to embryo transfer in freeze-all cycles of patients with endometriosis or aberrant endometrial integrin expression.

Prolonged gonadotrophin-releasing hormone agonist (GnRHa) administration before IVF with fresh embryo transfer to patients with endometriosis or aberrant endometrial integrin expression (-integrin) improves outcomes but may suppress ovarian response and prevents elective cryopreservation of all embryos. This retrospective cohort pilot study evaluates freeze-all cycles with subsequent prolonged GnRHa before embryo transfer in these populations. Patients from 2010 to 2015 who met inclusion criteria and received a long-acting GnRHa every 28 days twice before FET were evaluated. A subset underwent comprehensive chromosomal screening (CCS) after trophectoderm biopsy. Three groups were identified: Group 1: + CCS, +endometriosis (20 patients, 20 transfers); Group 2: +CCS, -integrin (12 patients, 13 transfers); Group 3: no CCS, +endometriosis or -integrin (10 patients, 12 transfers); Group 4: all transfers after CCS for descriptive comparison only (n = 2809). Baseline characteristics were similar among Groups 1-3 except that the mean surgery to oocyte aspiration interval was longer for Group 1 than Group 3. Implantation and ongoing pregnancy rates were statistically similar among the three groups and compared favourably to Group 4. A non-significant trend towards improved outcomes was noted in Group 1. Prolonged GnRHa after freeze-all in these patients avoids excessive ovarian suppression and results in excellent outcomes.

Endometriosis-Related Infertility: The Role of the Assisted Reproductive Technologies.

The assisted reproductive technologies, particularly in vitro fertilization (IVF), represent the most efficient and successful means of overcoming infertility associated with endometriosis. Although older studies suggest that IVF outcomes are compromised in endometriosis patients, more contemporary reports show no differences compared to controls. The exception may be evidence of poorer outcomes and diminished ovarian response in women with advanced disease, particularly those with significant ovarian involvement or prior ovarian surgery. Prolonged pre-IVF cycle suppressive medical therapy, particularly gonadotropin releasing hormone agonists, appears to improve success rates in a subset of endometriosis patients. However, as of yet, there is no diagnostic marker to specifically identify those who would most benefit from this approach. Pre-IVF cycle surgical resection of nonovarian disease has not been consistently shown to improve outcomes with the possible exception of resection of deeply invasive disease, although the data is limited. Precycle resection of ovarian endometriomas does not have benefit and should only be performed for gynecologic indications. Indeed, there is a large body of evidence to suggest that this procedure may have a deleterious impact on ovarian reserve and response. A dearth of appropriately designed trials makes development of definitive treatment paradigms challenging.

Endometriosis and assisted reproductive technologies: maximizing outcomes.

In vitro fertilization (IVF) represents the most efficient means of overcoming endometriosis-related infertility. Compromised pelvic anatomy and a hostile peritoneal environment are bypassed. Despite the results of early trials, more contemporary outcomes data would suggest that when controlled for age, IVF cycle outcome is not compromised by the presence of endometriosis. One exception to this concept is the finding that patients with ovarian endometriomas demonstrate poorer response to gonadotropin therapy, although it is not clear that this affects the likelihood of implantation. Surgical ablation of superficial endometriosis has no clear impact on IVF pregnancy rates, although a small number of recent trials suggest that pre-cycle resection of deeply infiltrative disease may be beneficial. With the exception of traditional gynecologic indications, there is no evidence to suggest that resection of ovarian endometriomas has any positive impact on cycle outcome. There are, in fact, data demonstrating that resection may exert a deleterious effect on ovarian reserve. A subset of patients will benefit from administration of a prolonged course of a gonadotropin-releasing hormone agonist prior to an IVF cycle. However, the characteristics of that subset have not been identified. It would be logical to consider this approach in women with more advanced disease, severe symptoms, and a history of implantation failure. Data on the impact of other pre-cycle medical interventions such as aromatase inhibitors, danazol, or oral contraceptives are more limited. There is also no evidence to suggest that the ovarian stimulation associated with IVF induces progression of endometriosis.

Association of abnormal ovarian reserve parameters with a higher incidence of aneuploid blastocysts.

OBJECTIVE: To estimate the relationship between hormonal parameters of diminished ovarian reserve and the incidence of aneuploid blastocysts. METHODS: This prospective cohort trial was performed in a private in vitro fertilization clinic. Three hundred seventy-two patients underwent in vitro fertilization with blastocyst biopsy and aneuploidy screening of all 23 chromosome pairs. Patients were divided into groups based on baseline hormonal ovarian reserve. Group 1 included normal ovarian reserve (n=279) and group 2 included diminished ovarian reserve with day 2 or 3 follicle-stimulating hormone (FSH) more than 10 milli-international units/mL, antimüllerian hormone 1 ng/mL or less (n=93), or both. Patients with diminished ovarian reserves were further subdivided into three groups. Group A included FSH more than 10 milli-international units and antimüllerian hormone 1 ng/mL or less (n=25); group B included FSH more than 10 milli-international units/mL and antimüllerian hormone more than 1 ng/mL (n=34); and group C included antimüllerian hormone 1 ng/mL or less and day 3 FSH less than 10 milli-international units/L (n=34). RESULTS: Group 2 (diminished ovarian reserve) had a higher percentage of aneuploid blastocysts (66% compared with 51.7%; P<.05) and all aneuploid blastocyst cycles (35.1% compared with 14.3%; P<.001) than group 1 (normal ovarian reserve). However, implantation rates after transfer of euploid blastocysts were similar (69% compared with 61.7%; not significant). The highest percentage of aneuploid blastocysts among diminished ovarian reserve patients was in group A (abnormal FSH and antimüllerian hormone) compared with groups B and C (77.2% compared with 58.5% compared with 58.8%; P<.05). Implantation rates also were no different among the diminished ovarian reserve subgroups (68% compared with 71% compared with 66.7%; not significant). CONCLUSIONS: Infertility patients with hormonal evidence of diminished ovarian reserve have a significantly higher percentage of aneuploid blastocysts. The combination of abnormal serum FSH and antimüllerian hormone correlated with the greatest rate of embryonic aneuploidy. Regardless of ovarian reserve parameters, transfer of euploid blastocysts resulted in equivalent implantation potential. LEVEL OF EVIDENCE: II.

Should diagnostic hysteroscopy be performed before in vitro fertilization-embryo transfer?

The role of routine uterine cavity evaluation before an in vitro fertilization-embryo transfer (IVF-ET) cycle has not been uniformly accepted. Published trials have demonstrated a relatively high incidence of cavitary abnormalities diagnosed at outpatient hysteroscopy in patients with previous IVF-ET cycle failure, the correction of which markedly improves outcomes. The value of performing this procedure before an initial cycle in patients without previous implantation failure has not been definitively confirmed in prospective randomized trials, but would seem logical in an effort to minimize the number of cycles a patient must undergo. The incidence of cavitary abnormalities in this population varies. One large series has reported a 22.9% incidence of endometrial cavitary abnormalities diagnosed at pre-cycle office hysteroscopy in this patient group. Hysterosalpingography and baseline transvaginal ultrasonography are insufficiently sensitive alternatives. Sonohysterography with infusion of saline solution, in particular with 3-dimensional technology, may be a reasonable alternative to diagnostic hysteroscopy, although relatively few well-designed trials have addressed this issue. There are an insufficient number of prospective randomized trials to clearly demonstrate that surgical removal of all abnormalities improves IVF-ET outcome. However, investigators suggest a benefit for resection of submucosal leiomyomas, adhesions, and at least a subset of polyps. Appropriately designed trials are required before a definitive recommendation can be made.

Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show?

PURPOSE OF REVIEW: Endometriosis is a gynecologic disorder that can lead to debilitating chronic pelvic pain and infertility. Gonadotropin-releasing hormone agonists (GnRHa) have emerged as a primary medical therapy for patients with symptomatic disease, but secondary hypoestrogenic side effects may limit compliance. Add-back therapy is a means of surmounting this problem. RECENT FINDINGS: Progestins such as norethindrone acetate may be administered with or without addition of low doses of estrogens to safely and effectively extend GnRHa therapy while minimizing side effects. Recent studies have demonstrated that the use of add-back enhances compliance and duration of therapy. The initiation of an add-back should not be deferred given evidence demonstrating an increase in vasomotor symptoms and bone loss if not administered concomitantly. The subset of adolescents with endometriosis who require GnRHa therapy should be administered an add-back, but require careful monitoring of bone mineral density. SUMMARY: Implementation of an appropriately selected add-back will significantly reduce hypoestrogenic side effects, enhance compliance, and allow for prolongation of therapy without interfering with the efficacy of GnRHa in treating symptomatic endometriosis.

Does endometrial integrin expression in endometriosis patients predict enhanced in vitro fertilization cycle outcomes after prolonged GnRH agonist therapy?

OBJECTIVE: To determine whether endometrial expression of the integrin alpha(v)beta(3) vitronectin can predict which endometriosis patient subgroup will benefit from pre-IVF cycle prolonged GnRH agonist (GnRHa) therapy. DESIGN: Prospective randomized institutional review board approved pilot trial. SETTING: Private assisted reproductive technology program. PATIENT(S): IVF candidates with regular menses, surgically confirmed endometriosis, and normal ovarian reserve. INTERVENTION(S): All patients underwent endometrial biopsy 9 to 11 days post-LH surge to evaluate alpha(v)beta(3) integrin expression. Patients were randomized either to receive depot leuprolide acetate 3.75 mg every 28 days for three doses before controlled ovarian hyperstimulation (COH) or to proceed directly to COH and IVF. Group 1: integrin-positive controls (N = 12); group 2: integrin-positive administered prolonged GnRHa (N = 8). Group A: integrin-negative controls (N = 7); group B: integrin-negative administered prolonged GnRHa (N = 9). MAIN OUTCOME MEASURE(S): COH responses, ongoing pregnancy and implantation rates. RESULTS: There were no significant effects of GnRH agonist treatment in either of the integrin expression strata regarding ongoing pregnancy or implantation rates, although these outcomes were more frequent in group 2 vs. 1 (62.5% vs. 41.6% and 35% vs. 20.6%, respectively). This effect may have because of limited sample size. The value of a negative integrin biopsy in predicting an ongoing pregnancy after prolonged GnRH agonist therapy was only 44.4%. CONCLUSION(S): Endometrial alpha(v)beta(3) integrin expression did not predict which endometriosis patients would benefit from prolonged GnRHa therapy before IVF.

Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol?

OBJECTIVE: To compare the efficacy of a microdose GnRH agonist flare (ML) with a GnRH antagonist/letrozole (AL) protocol before IVF-ET in poor responders. DESIGN: Prospective controlled trial. SETTING: Private assisted reproductive technology center. PATIENT(S): Five hundred thirty-four infertile women classified as past or potential poor responders based on clinic-specific criteria. INTERVENTION(S): Poor responders were prospectively assigned to an ML or AL protocol in a 2:1 ratio, respectively. MAIN OUTCOME MEASURE(S): Results of controlled ovarian hyperstimulation and implantation and ongoing pregnancy rates. RESULT(S): Patient characteristics were similar between the two protocol groups. There were no significant differences in mean age, number of oocytes, fertilization rates, number of embryos transferred, or embryo score. Peak E(2) levels were significantly lower in the AL group. Ongoing pregnancy rates were significantly higher in the ML group (52% vs. 37%). Trends toward increased implantation and lower cancellation rates were also noted, but these did not reach statistical significance. CONCLUSION(S): Quantitative results of stimulation between the ML and AL protocols were equivalent with the exception of peak E(2) levels. However, the higher ongoing pregnancy rates and trend toward superior implantation rates would suggest that ML represents a preferred approach for the poor responder. An increased sample size would be necessary to verify these findings.

Management of the poor responder: the role of GnRH agonists and antagonists.

PURPOSE: Evaluate the relative benefit of various doses and regimens of GnRH agonists (GnRHa) and antagonists (GnRHant) in the management of the poor responder. METHODS: Review of English language publications with an emphasis on prospective randomized trials where available. RESULTS: The lack of a uniformly applied definition of the poor responder and dearth of prospective randomized trials make data analysis difficult. Traditional GnRHa flare and long luteal phase protocols do not appear to be beneficial. Reduction of GnRHa doses, "stop" protocols, and microdose GnRHa flare regimes all appear to enhance outcomes, although the relative benefit of one approach over another has not been conclusively demonstrated. GnRHant does improve outcomes in this patient population, although, in general, pregnancy rates appear to be lower in comparison to microdose GnRHa flare regimes. CONCLUSIONS: There is no one controlled ovarian hyperstimulation (COH) protocol which is best suited for all poor responders. Low dose GnRHa regimes appear to be most advantageous. Prediction of compromised response prior to cycle initiation by a thorough assessment of ovarian reserve as well as a careful review of past response should allow for selection of an appropriate COH protocol for each individual patient.