Keith B. Isaacson

Impact of varying stages of endometriosis on the outcome of in vitro fertilization-embryo transfer.

Purpose:The impact of severity of endometriosis on the outcome of in vitro fertilization (IVF) was analyzed in an uncontrolled, retrospective study in an academic IVF program.Methods:Sixty-one patients with a primary diagnosis of endometriosis undergoing 85 cycles of IVF were included in the study. Patients were divided according to the severity of disease based on the revised American Fertility Society (AFS) classification into groups A (stages I/II, or minimal/mild) and B (stages III/IV, or moderate/severe). Group A included 32 patients undergoing 45 IVF-embryo transfer (ET) cycles; group B included 29 patients undergoing 40 IVF cycles. Exclusion criteria were age older than 40 years, basal day 3 follicle stimulating hormone (FSH) greater than 20 IU/L, male-factor infertility, assisted hatching, and gamete intrafallopian transfer cases. Stimulation for IVF cycles was standard using pituitary down-regulation with gonadotropin-releasing hormone agonist in a midluteal protocol. Controlled ovarian hyperstimulation (COH) was achieved using a combination of FSH and human menopausal gonadotropin. Outcomes assessed included response to COH and number, maturity, and quality of oocytes retrieved. Fertilization, implantation, and pregnancy rates after IVF-ET were also analyzed.Results:The response to COH and the number, maturity, and quality of the oocytes was comparable between patients with varying severity of endometriosis. Fertilization rates for oocytes of patients in group B (stages III/IV) were significantly impaired compared to those in group A (stages I/II) (P = 0,004). The rates for implantation, clinical pregnancy, and miscarriage were comparable between the two groups.Conclusions:The reduced fertilization potential of the oocytes obtained from patients with severe endometriosis in the absence of male-factor infertility suggests an adverse biological impact of the advanced disease on the oocytes. The outcome of IVF-ET, however, is unaffected by increasing severity of endometriosis. This suggests that IVF may compensate for or overcome this reduction in the biological potential of the oocytes associated with severe disease, thus accounting for a comparable outcome irrespective of the severity of endometriosis.

CLINICAL ASSISTED REPRODUCTION: Antral Follicle Assessment as a Tool for Predicting Outcome in IVF—Is it a Better Predictor than Age and FSH?

Purpose: The purpose of this study is to determine if baseline antral follicle assessment may serve as additional information in predicting in vitro fertilization outcome.Methods: Prospective, descriptive preliminary study of in vitro fertilization outcome. From July 1998 to July 1999, 224 patients underwent antral follicle assessment (follicle 2–6 mm in diameter) on baseline of the planned, stimulated in vitro fertilization cycle. The outcomes were analyzed with respect to antral follicle assessment (≤6 or >6), basal cycle day 3 follicle stimulated harmone (≤10 or >10 IU/L) and maternal age (≤35 or >35 years).Results: The clinical pregnancy rate was significantly higher in the group with baseline antral follicle >6 compared to that in the group with antral follicle ≥6 (51% vs. 19%, respectively). Controlling for patient age, and basal follicle stimulated harmone, the pregnancy rate was significantly higher in the group with antral follicle >6 compared to that in the group with antral follicle ≤6. The cancellation rate was significantly increased with advancing maternal age, elevated basal follicle stimulated harmone levels, and baseline antral follicle ≤6. The cancellation rate was significantly higher in the group with antral follicle ≤6 compared to that in the group with antral follicle ≥6 (33% vs. 1%, respectively).Conclusions: In vitro fertilization outcome is strongly correlated with both maternal ages, basal cycle, day 3 follicle, stimulated harmone, and antral follicle assessment. Antral follicle assessment was a better predictor of in vitro fertilization outcome than were age or follicle stimulated harmone. Antral follicle assessment may provide a marker for ovarian age that is distinct from chronological age or hormonal markers.

Endometrial synthesis and secretion of complement component-3 by patients with and without endometriosis * †

In the present study we examined complement-3 (C3) synthesis and secretion from early proliferative endometrium of infertile patients with and without endometriosis. One gram of tissue was obtained by endometrial sampling at the time of diagnostic laparoscopy and incubated for 12 to 16 hours in the presence of radioactive methionine. Immunoprecipitation was performed with rabbit antihuman C3 immunoglobulin G and only a single 180-kDa radiolabeled protein (C3) was immunoprecipitated. This protein dissociates into 113- and 69-kDa subunits in the presence of dithiothreitol. The amount of C3 produced and secreted by the endometrium was quantitated as a percentage of counts per minute recovered by immunoprecipitation. Patients with minimal endometriosis produced significantly greater amounts of endometrial C3 than patients with no endometriosis or patients with severe endometriosis.

Adenomyosis: review of the literature.

Adenomyosis usually occurs in women in their reproductive years, predominantly in those with menorrhagia and dysmenorrhea. The etiology and pathophysiology remain unclear; however, recent advancements in diagnostic methods and new investigations of treatment options have changed how clinicians manage adenomyosis. A review was performed using PubMed and cross-references of reviews, case reports, and prospective and retrospective studies published from 1958 to 2010 to provide an overview of the etiology, diagnosis, prevalence, risk factors, clinical signs and symptoms, and treatments of adenomyosis.

ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling

Significance Regulated cell-surface proteolysis underpins processes of cellular migration in both physiological and pathological contexts. However, comprehending how multiple proteolytic events cohesively integrate to yield context-dependent cellular behavior remains a challenge. Here we present an experimental/computational paradigm for analyzing networks of protease activities that interface with signaling pathways to influence cellular migration in the invasive disease of endometriosis. We find that induced cellular migration is a quantitative consequence of positive feedback through ligand release and negative feedback through receptor shedding, which furthermore drives rapid resistance to kinase inhibitor treatment. Targeted clinical proteomics confirms dysregulated proteolysis in endometriosis. A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM “sheddase” function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor–driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.

COMPLICATIONS OF HYSTEROSCOPY

Most of the complications of hysteroscopy are avoidable and, fortunately, rare. With improved training, experience, and technology, most of these complications should become extinct. There will always be some unavoidable complications as well as difficulties resulting from inexperience. A goal for the future is to teach operating room personnel how to recognize and treat these complications to ensure the best patient outcome possible. Once gynecologic surgeons recognize the safety and efficacy of diagnostic and operative hysteroscopy as a minimally invasive option to treat benign uterine pathology, these procedures will proliferate and result in better patient care and improved quality of life.

Postoperative adhesiolysis therapy for intrauterine adhesions (Asherman's syndrome)

OBJECTIVE To evaluate postoperative blunt adhesiolysis after sharp adhesiolysis for the treatment of intrauterine adhesions. DESIGN Retrospective analysis of 24 patients treated with primary hysteroscopic adhesiolysis followed by hormone therapy and serial flexible office hysteroscopy (Canadian Task Force Classification II-3). SETTING University-affiliated community hospital. PATIENT(S) Twenty-four women with menstrual disorders, pain, or infertility resulting from intrauterine adhesions. INTERVENTION(S) Serial, postoperative, hysteroscopic blunt adhesiolysis of recurrent synechiae. MAIN OUTCOME MEASURE(S) Restoration of normal menstrual pattern, relief of dysmenorrhea, improvement in fertility, and improvement in stage of disease. RESULT(S) Eighty-three percent of patients (20/24) presented with amenorrhea or oligomenorrhea, 67% (16/24) had either infertility or recurrent miscarriages, and 54% (13/24) presented with dysmenorrhea. Initially, 50% (12/24) had severe adhesions, 46% (11/24) moderate, and 4% (1/24) minimal disease according to the March criteria. Improvement in menstrual flow occurred in 95% (18/19) of patients, relief of dysmenorrhea occurred in 92% (12/13), and 46% (7/15) of fertility patients were actively pregnant or had delivered viable infants at the conclusion of the study. There was a 92% (22/24) improvement in disease staging over the treatment interval. CONCLUSION(S) Blunt adhesiolysis with a flexible hysteroscope is effective for maintenance of cavity patency after primary treatment of intrauterine adhesions.

Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation.

The molecular correlates of heterogeneous endometriosis symptoms support a role for innate inflammatory responses converging upon c-Jun and NFκB signaling cascades. Endometriosis: Embracing Complexity Despite its widespread contribution to infertility and debilitating pelvic pain, treatments for endometriosis—an invasive displacement of endometrial tissue outside the uterus—primarily address symptoms and fall short on combating the underlying disease. Avenues for targeted intervention have been lacking, in part due to significant patient heterogeneity that hampers reproducible findings across diverse study populations. To overcome this hurdle, Beste et al. have applied a data-driven strategy to uncover the natural variation in pelvic inflammatory status across a broad cohort of endometriosis patients. By naïvely characterizing comprehensive molecular profiles for each patient, the authors were able to identify a coherent signature of macrophage activity that was otherwise obscured by conventional staging criteria. Further experiments on isolated macrophages revealed a refined signature that unexpectedly implicated the c-Jun N-terminal kinase (JNK) signaling pathway. By confirming that small-molecule inhibition of JNK signaling broadly curbed macrophage inflammatory activity, this work provides a possible lead for future experimental and clinical studies into curtailing the deleterious inflammatory response to endometriotic lesions. If this general approach is validated in larger populations, such profiles may also be helpful as a complementary tool to better identify patients at greater risk for recurrence who would benefit from aggressive treatment. Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentation, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify new approaches to targeted treatment. We use a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient subpopulations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared “consensus signature” of 13 elevated cytokines that was associated with common clinical features of endometriosis, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the nuclear factor κB family emerged among overrepresented transcriptional binding sites for consensus markers, our analysis provides evidence for an unexpected contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen-associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses suggest a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of new agents aimed at curtailing inflammatory mechanisms that drive disease progression.

Outcome and resource use associated with myomectomy.

OBJECTIVE To evaluate the outcomes and cost of myomectomy through retrospective claims data analysis. METHODS The study was performed using a retrospective database of private insurance claims from 1995 to 1997. Records were selected for analysis based on the presence of ICD‐9‐CM procedure and/or CPT‐4 codes associated with myomectomy. In addition, diagnosis of uterine leiomyoma and related symptoms for these patients were confirmed through ICD‐9‐CM diagnosis codes. Inpatient, outpatient, and physician costs were estimated. All cost data were converted into 1997 dollars. RESULTS A total of 4394 women, between the ages of 14 and 70, were available for analysis. Of these, 3305 were classified by type of myomectomy procedure, and complete data were available on 820 at 1 year and 236 at 2 years. Abdominal myomectomies were the most common procedures, followed by hysteroscopic and laparoscopic myomectomies. Conversion to a more invasive procedure occurred in 5.4% of the patients. The rate of additional surgeries was 8.3% in 6 months, 10.6% in 1 year, and 16.5% in 2 years. Overall cost increased from an initial

Treatment of Congenital Malformations

6,737 per patient to