Comparing Characteristics of and Postoperative Morbidity after Hysterectomy for Endometriosis versus other Benign Indications: A NSQIP Study.

STUDY OBJECTIVE: Compare the difference in postoperative morbidity for benign total hysterectomy by indication. DESIGN: Retrospective cohort. SETTING: United States hospitals participating in the American College of Surgeons National Surgical Quality Improvement Project database from 2018 to 2019. PATIENTS: Patients undergoing total hysterectomy for benign indications age 18 to 55 years old. INTERVENTIONS: Univariate comparisons were made between patients with hysterectomies for endometriosis and other benign indications. Unadjusted and adjusted logistic regression models were used to investigate the association between primary outcomes and hysterectomy indication; covariates in the adjusted model include age, race, ethnicity, and route. MEASUREMENTS AND MAIN RESULTS: A total of 29 742 women underwent hysterectomies, of which 3596 (12.1%) were performed for endometriosis. Patients undergoing hysterectomy for endometriosis were likely to be younger, were predominately White, and had less comorbidities. They were also more likely to have previous abdominal surgery, have previous pelvic surgery, undergo a laparoscopic approach, and undergo lysis of adhesions (all p <.001). Overall length of stay (≥1 day 73.1% vs 78.6%; p = .983) and operative time (median 118.0 vs 125.0 minutes; p <.001) were similar in both groups. Examining primary outcomes, patients with endometriosis were more likely to experience major morbidity (3.8% vs 3.4%; adjusted odds ratio [OR], 1.25; p = .033), with no difference in minor or overall morbidity (5.8% vs 6.9% [p = .874] and 8.8% vs 9.4% [p = .185], respectively). There were two 30-day mortalities, none in the endometriosis group. Patients with endometriosis were more likely to develop deep surgical site infection (SSI)/organ-space infection (2.3% vs 1.6%; OR, 1.42; p = .024) and less likely to receive blood transfusion (1.8% vs 3.0%; OR, 0.58; p <.001). There was no difference in occurrence of superficial SSI, sepsis, venous thromboembolism, readmission, or reoperation between groups. CONCLUSION: Patients undergoing hysterectomy for endometriosis were more likely to experience major morbidity and deep SSI, although overall major morbidity is rare.

The expression of pregnancy-associated plasma protein-A (PAPP-A) in human blastocoel fluid-conditioned media: a proof of concept study.

PURPOSE: The aim of this study was to determine if pregnancy-associated plasma protein-A (PAPP-A), typically measured in maternal serum and a potential predictor of adverse maternal and fetal outcomes such as spontaneous miscarriage, pre-eclampsia, and stillbirth, is expressed in blastocoel fluid-conditioned media (BFCM) at the embryonic blastocyst stage. DESIGN: This is an in vitro study. METHODS: BFCM samples from trophectoderm-tested euploid blastocysts (n = 80) from in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) patients were analyzed for PAPP-A mRNA. BFCM was obtained from blastocyst stage embryos in 20 uL drops. Blastocysts underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy prior to blastocyst vitrification and BFCM collection for snap freezing. cfDNA was synthesized using BFCM collected from 80 individual euploid blastocysts. Next, real-time qPCR was performed to detect expression of PAPP-A with GAPDH for normalization of expression in each sample. RESULTS: PAPP-A mRNA was detected in 45 of 80 BFCM samples (56.3%), with varying levels of expression across samples. CONCLUSION: Our study demonstrates the expression of PAPP-A in BFCM. To our knowledge, this is the first study to report detection of PAPP-A mRNA in BFCM. Further studies are required and underway to investigate a greater number of BFCM samples as well as the possible correlation of PAPP-A expression with pregnancy outcomes of transferred euploid blastocysts. If found to predict IVF and obstetric outcomes, PAPP-A may provide additional information along with embryonic euploidy for the selection of the optimal blastocyst for embryo transfer.

The effects of hysteroscopic morcellation of endometrial polyps on frozen embryo transfer outcomes.

OBJECTIVE(S): To determine if hysteroscopic removal of endometrial polyps, specifically via morcellation of polyps, affects implantation rate (IR), clinical pregnancy rate (CPR), spontaneous abortion (SAB) rate, and live birth rate (LBR) in first frozen embryo transfer (FET) cycles. STUDY DESIGN: Retrospective chart review, with data abstracted from the charts of all first autologous oocyte frozen embryo transfer (FET) cases (n = 135) at a single fertility center from January 2018 through June 2020. Subjects were grouped into (A) hysteroscopic polypectomy prior to first FET (n = 25) or (B) no hysteroscopic polypectomy prior to first FET (n = 110). The primary outcome was live birth rate (LBR). Secondary outcomes were implantation rate (IR), clinical pregnancy rate (CPR), and spontaneous abortion (SAB) rate. RESULTS: We found no difference between the groups in terms of the primary outcome (LBR) or the secondary outcomes IR, CPR, and SAB rate. CONCLUSION(S): The data analyzed here suggest that hysteroscopic morcellation of endometrial polyps has no adverse effect on IR, SAB rate, CPR, or LBR among first FET cases after this type of polypectomy.

FSH levels and testicular volumes are associated with the severity of testicular histopathology in men with non-obstructive azoospermia.

PURPOSE: The purpose of this study is to assess a potential association between FSH levels and testicular volumes with the severity of testicular histopathology on testicular biopsy in men with non-obstructive azoospermia (NOA) undergoing microdissection testicular sperm extraction (microTESE). METHODS: A retrospective chart review was performed from the electronic health records of men who underwent microTESE with NOA. RESULTS: Eighty-six men with NOA underwent microTESE with concomitant testicular biopsy for permanent section to assess the testicular cellular architecture. The histopathological patterns were categorized by severity indicating the odds of sperm retrieval into 2 categories. The unfavorable category included Sertoli cell only pattern and early maturation arrest (n = 50) and the favorable category included late maturation arrest and hypospermatogenesis patterns (n = 36). In the men with unfavorable histopathologic patterns, the mean FSH level was 22.9 ± 16.6 IU/L, and the mean testicular volume was 10.4 ± 6.0 cc. This was in comparison to men with favorable histopathologic patterns revealing a mean FSH level of FSH 13.3 ± 12.0 with a mean testicular volume of 13.3 ± 5.9 cc. There was a statistically significant higher FSH level in men with unfavorable histopathology than favorable (p = 0.004) as well as a significant smaller mean testicular volume in men with unfavorable histopathology (p = 0.029). CONCLUSIONS: Higher serum FSH levels and smaller testicular volumes are associated with more severe testicular histopathological patterns in men with NOA.

Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways.

Despite an estimated prevalence of 11% in women and plausible historical descriptions dating back to the 17th century, the etiology of endometriosis remains poorly understood. Classical theories of the histological origins of endometriosis are reviewed below. Clinical presentations are variable, and signs and symptoms do not correlate well with the extent of disease. In this summary, we have attempted to synthesize the growing evidence that hormonal and immune factors conspire to activate a local inflammatory microenvironment that encourages endometriosis to persist and elaborate mediators of its two cardinal symptoms: pain and infertility. Surprisingly, in the search for novel therapeutics for medical treatment of endometriosis, some compounds appear to have dual pharmacological functions, simultaneously modifying the endocrine and immune system facets of this complex gynecologic syndrome. We predict that these lead drugs will provide more therapeutic choices for patients in the future.

New paradigms in the diagnosis and management of endometriosis.

PURPOSE OF REVIEW: Endometriosis is a common gynecologic condition estimated to affect 10-15% of reproductive-aged women, 30% of women with subfertility, and 80% of women with chronic pelvic pain. Although mainstays of diagnosis and treatment are still commonly applied, there have been various advances in the modalities of diagnosis and management of this complex condition. This article provides an updated review of novel findings regarding the diagnosis and management of this challenging disease. RECENT FINDINGS: Despite an abundance of studies on noninvasive diagnostic markers for endometriosis, there is no single imaging study, biomarker or panel of biomarkers that has been validated for clinical diagnosis. New technologies, such as use of indocyanine green and fluorescence, which visualize neovascularization often associated with endometriosis may improve diagnostic detection of endometriosis at the time surgery, but have not been demonstrated to improve pain outcomes after surgery. Hormone suppression remains the mainstay therapy prior to and following surgery. Although most methods demonstrate similar efficacy in reducing endometriosis-associated pain, newer pharmacologic agents that may prove advantageous include oral gonadotropin receptor antagonists, selective progesterone receptor modulators, and angiogenesis inhibitors. SUMMARY: Although there have been some advances in the study of noninvasive imaging and biomarkers, more investigation into effective modalities are being conducted and are needed.

Effect of surgery for endometrioma on ovarian function.

Endometriosis affects a significant proportion of reproductive-aged women. The impact of the disease on ovarian function is an important consideration when planning treatment in women who want to retain the potential of future childbearing. This review will specifically address the association between endometriomas and diminished ovarian reserve, with a particular focus on the impact of surgical endometrioma resection on ovarian function. The existing literature supports an adverse effect of ovarian endometriomas on spontaneous ovulation rates, markers of ovarian reserve, and response to ovarian stimulation, although data on clinical pregnancy and live birth rates remain inconsistent. Surgical removal of endometriomas may worsen ovarian function by removing healthy ovarian cortex or compromising blood flow to the ovary. It is evident that surgical excision of endometriomas acutely impairs ovarian function as measured by ovarian reserve markers; whether this represents progressive or long term impairment remains the subject of ongoing investigation.

Robotic-assisted tubal anastomosis with one-stitch technique.

The da Vinci(®) robotic surgical system has been used more often in recent years for tubal anastomosis (TA) and has been reported to have an increased operative time. A one-stitch technique has been used for the reanastomosis step in laparoscopic TA. To date, publications on robotically-assisted TA (RATA) describe an anastomotic step with multiple (usually four) sutures placed. This retrospective case series reports tubal patency data on patients who underwent RATA with the one-stitch technique; tubal patency was the outcome measure. Eighteen women (ages 27-39) underwent RATA with the one-stitch anastomotic technique in tertiary care medical centers between February 2009 and May 2012. Tubal patency was demonstrated in 16/17 patients (94.1 %), as evidenced by postoperative hysterosalpingogram (HSG) and/or subsequent pregnancies. We report the first case series which shows that RATA with a single stitch for the reanastomotic step is effective in achieving tubal patency as evidenced by postoperative HSG and/or pregnancies.

PPARγ activation inhibits growth and survival of human endometriotic cells by suppressing estrogen biosynthesis and PGE2 signaling.

Endometriosis is a chronic inflammatory disease of reproductive age women leading to chronic pelvic pain and infertility. Current antiestrogen therapies are temporizing measures, and endometriosis often recurs. Potential nonestrogenic or nonsteroidal targets are needed for treating endometriosis. Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear receptor, is activated by thiazolidinediones (TZDs). In experimental endometriosis, TZDs inhibit growth of endometriosis. Clinical data suggest potential use of TZDs for treating pain and fertility concurrently in endometriosis patients. Study objectives were to 1) determine the effects of PPARγ action on growth and survival of human endometriotic epithelial and stromal cells and 2) identify the underlying molecular links between PPARγ activation and cell cycle regulation, apoptosis, estrogen biosynthesis, and prostaglandin E2 biosynthesis and signaling in human endometriotic epithelial and stromal cells. Results indicate that activation of PPARγ by TZD ciglitazone 1) inhibits growth of endometriotic epithelial cells 12Z up to 35% and growth of endometriotic stromal cells 22B up to 70% through altered cell cycle regulation and intrinsic apoptosis, 2) decreases expression of PGE2 receptors (EP)2 and EP4 mRNAs in 12Z and 22B cells, and 3) inhibits expression and function of P450 aromatase mRNA and protein and estrone production in 12Z and 22B cells through EP2 and EP4 in a stromal-epithelial cell-specific manner. Collectively, these results indicate that PGE2 receptors EP2 and EP4 mediate actions of PPARγ by incorporating multiple cell signaling pathways. Activation of PPARγ combined with inhibition of EP2 and EP4 may emerge as novel nonsteroidal therapeutic targets for endometriosis-associated pain and infertility, if clinically proven safe and efficacious.

Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects.

The endometrium is ground zero when it comes to understanding how implantation occurs and how it might also fail, resulting in infertility or pregnancy loss. Many of the causes of diminished uterine receptivity are acquired during a woman's lifetime. Endometriosis, a major inflammatory disease affecting women, is also a leading cause of infertility and miscarriage. Once established, the inflammatory changes can, in some women, lead to progesterone resistance and downstream changes in endometrial gene expression. Much is now known about how inflammation translates to progesterone resistance and infertility, but much remains to be learned. In this review we provide an overview for understanding how the endometrium becomes dysfunctional, what biomarkers may hold promise for the diagnosis of endometriosis, and how progesterone resistance leads to infertility. Understanding the pathophysiology of this disease will likely lead to better treatment options.

Clinical management of endometriosis.

Endometriosis is a relatively common chronic gynecologic disorder that usually presents with chronic pelvic pain or infertility. The societal effect of this disorder is enormous both in monetary costs and in quality of life. The diagnosis of the disease can only be definitively made with surgical intervention. Fertility may be enhanced with surgical intervention, but medical suppressive therapy has no role apart from in vitro fertilization. Assisted reproductive technology is associated with excellent outcomes. Management of endometriomas is particularly complex because surgical intervention may reduce ovarian reserve. Both medical and surgical treatment of endometriosis-associated chronic pelvic pain are effective in the short-term. Recurrence is common with both modalities. Recurrence after surgical intervention can be decreased with the use of postoperative suppressive medical therapy such as hormonal contraceptives. This article presents the different types of peritoneal disease found in endometriosis patients. The technique used to safely and completely remove the disease is discussed. The specific areas of involvement include the pelvic side wall, the cul-de-sac, and bladder peritoneum.

Development and prevention of postsurgical adhesions in a chimeric mouse model of experimental endometriosis.

OBJECTIVE: To examine the impact of a recent surgery on development of endometriosis-related adhesions in a chimeric model and to determine the therapeutic efficacy of pioglitazone (PIO). DESIGN: Human endometrial biopsies were maintained in E(2) with or without PIO for 24 h before intraperitoneal injection into immunocompromised mice also treated with or without PIO at multiple time points after peritoneal surgery. The presence and extent of adhesions were examined in animals relative to the initial establishment of experimental endometriosis. SETTING: Medical school research center. PATIENT(S): Endometrial biopsies for experimental studies were provided by normally cycling women without a medical history indicative of endometriosis or adhesions. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Examination of the development of endometriosis-related adhesions in an experimental model. RESULT(S): Without therapeutic intervention, injection of E(2)-treated human endometrial tissue into mice near the time of peritoneal surgery resulted in multiple adhesions and extensive endometriotic-like disease. In contrast, PIO treatment reduced adhesive disease and experimental endometriosis related to surgical injury. CONCLUSION(S): The presence of human endometrial tissue fragments in the peritoneal cavity of mice with a recent surgical injury promoted development of both adhesive disease and experimental endometriosis. Targeting inflammation and angiogenesis with PIO therapy limited the development of postsurgical adhesions associated with ectopic endometrial growth.

Peroxisome proliferator-activated receptor-(gamma) receptor ligand partially prevents the development of endometrial explants in baboons: a prospective, randomized, placebo-controlled study.

A prospective, randomized, placebo-controlled study was conducted in a baboon model to determine if a thiazolidinedione agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone, can impede the development of endometriosis. Endometriosis was induced using laparoscopic, intrapelvic injection of eutopic menstrual endometrium, previously incubated with placebo or pioglitazone for 30 min, in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity. At this point, the 12 baboons were randomized into two groups and treated from the day of induction. They received either PBS tablets (n = 6, placebo control, placebo tablets once a day by mouth) or pioglitazone (n = 6, test drug, 7.5 mg by mouth each day). A second and final laparoscopy was performed in the baboons to record the extent of endometriotic lesions between 24 and 42 d after induction (no difference in length of treatment between the two groups, P = 0.38). A videolaparoscopy was performed to document the number and surface area of endometriotic lesions. The surface area and volume of endometriotic lesions were significantly lower in pioglitazone treated baboons than the placebo group (surface area, 48.6 vs. 159.0 mm(2), respectively, P = 0.049; vol, 23.7 vs. 131.8 mm(3), respectively, P = 0.041). The surface area (3.5 vs. 17.8 mm(2), P = 0.017, pioglizatone vs. placebo) and overall number (1.5 vs. 9.5, P = 0.007, pioglizatone vs. placebo) of red lesions were lower in the pioglitazone group. A peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, effectively reduced the initiation of endometriotic disease in the baboon endometriosis model. Using this animal model, we have shown that thiazolidinedione is a promising drug for preventive treatment of endometriosis.

Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro.

OBJECTIVE: To determine the effect of thiazolidenedione derivatives (TZDs) on vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells and the morphologic development of murine embryos. DESIGN: Prospective, experimental, in vitro and in vivo study. SETTING: Research laboratory. PATIENT(S): Follicular aspirates from 10 women undergoing oocyte retrieval. INTERVENTION(S): Isolated human granulosa cells were treated with a dimethyl sulfoxide (DMSO) control or ciglitazone, in the presence and absence of an hCG stimulus. Embryos extracted from superovulated B6C3F1 female mice were cultured in the presence of DMSO or pioglitazone. MAIN OUTCOME MEASURE(S): Vascular endothelial growth factor concentrations at 24 and 48 hours. Morphologic development of murine embryos at 96 hours. RESULT(S): Following an hCG stimulus, treatment with 20 microM or 40 microM ciglitazone decreased VEGF production in a statistically significant manner at both time intervals. Blastocyst development at 96 hours did not significantly differ between untreated zygotes and those treated with pioglitazone. CONCLUSION(S): Ciglitazone significantly decreased VEGF production by human granulosa cells in an in vitro model. Pioglitazone did not adversely impact the development of cultured murine embryos. Although mechanistic evidence is not provided, the pivotal role of VEGF in ovarian hyperstimulation syndrome prompts investigation of TZDs as a novel treatment for this condition.

Endometriosis-associated nerve fibers and pain.

The assessment and diagnosis of endometriosis remain elusive targets. Patient and medical-related factors add to delays in the detection and treatment. Recently, investigators have revealed specific nerve fibers present in endometriotic tissue, with existing parallels between density and pain severity. The aim of this review is to compile a comprehensive review of existing literature on endometriosis-related nerve fiber detection, and the effects of medical therapy on these neural fibers. We performed a systematic literature-based review using Medline and PubMed of nerve fibers detected in eutopic endometrium, endometriotic lesions, and the peritoneum. Various arrangements of significant medical terms and phrases consisting of endometriosis, pelvic pain, nerve fiber detection/density in endometriosis, and diagnoses methodology, including treatment and detection were applied in the search. Subsequent references used were cross-matched with existing sources to compile all additional similar reports. Similar nerve fibers were detected within lesions, endometrium, and myometrium, though at varying degrees of density. Hormonal therapy is widely used to treat endometriosis and was shown to be related to a reduction in fiber density. A direct result of specific nerve fiber detection within eutopic endometrial layers points to the use of a minimally invasive endometrial biopsy technique in reducing delay in diagnosis and subsequent possible preservation of fertility.

PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: a prospective, randomized, placebo- and drug-controlled study.

OBJECTIVE: To determine the effects of a thiazolidinedione (TZD) agonist of peroxisome proliferator-activated receptor (PPAR)-gamma, rosiglitazone, in a baboon model of established endometriosis. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Experimental surgery laboratory at the Institute of Primate Research in Nairobi, Kenya. ANIMAL(S): Endometriosis was induced using intrapelvic injection of eutopic menstrual endometrium in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity. INTERVENTION(S): Induction of endometriosis by laparoscopy was performed in 12 baboons with a normal pelvis. Endometrial tissue was extracted from each baboon by curettage, and a standard amount of endometrium was then seeded onto several peritoneal sites. About 34-68 days after the induction of laparoscopy, a pretreatment laparoscopy (baseline disease assessment) was performed in the baboons to record the extent of endometriotic lesions. The 12 baboons were randomized into three groups and treated from the day after the staging laparoscopy for a total duration of 30 days. They received phosphate-buffered saline tablets (n = 4, placebo control; placebo tablets once a day by mouth for 30 days), GnRH-antagonists (n = 4, active control; ganirelix acetate 125 microg/day for 30 days), or rosiglitazone (n = 4, test drug, 2 mg by mouth each day for 30 days). A third and final laparoscopy on day 30 after the start of treatment was performed to record the extent of endometriosis. The type of lesion (typical, red, white, or suspicious) was recorded. Biopsies were obtained to confirm the histological presence of endometriosis. MAIN OUTCOME MEASURE(S): A videolaparoscopy was performed 30 days after treatment to document the number and surface area of endometriotic lesions as well as to calculate the revised American Society for Reproductive Medicine score and stage. RESULT(S): The surface area of endometriotic lesions was statistically significantly lower in rosiglitazone-treated baboons when compared with the placebo group. Baboons treated with rosiglitazone or ganirelix had a greater negative relative change in surface area of peritoneal endometriotic lesions than controls. The overall weighted appearance of the lesion types suggests that rosiglitazone may deter the development of newer endometriotic lesions. CONCLUSION(S): A PPAR-gamma ligand, rosiglitazone, effectively diminishes the burden of endometriosis disease in a baboon endometriosis model. This animal model holds promise that a TZD drug may be helpful in women with endometriosis.

Endometrioma complicated by tubo-ovarian abscess in a woman with bacterial vaginosis.

BACKGROUND: Tubo-ovarian abscess involvement of an endometrioma has been reported in cases of patients with polymicrobial sources such as Neisseria gonorrhoeae, Chlamydia trachomatis, and obligate anaerobic bacteria; however, bacterial vaginosis (BV) predisposing to abscess formation in an endometrioma has not been reported to date. CASE: Superinfection of an endometrioma was surgically diagnosed in a patient with known advanced-stage endometriosis after she presented with acute pelvic inflammatory disease symptoms and was unresponsive to antibiotic therapy. Gram-negative rods were cultured from the endometrioma. On admission, cervical, blood, and urine cultures were negative; BV was diagnosed on normal saline wet prep and gram stain. CONCLUSION: This case raises the possibility of BV ascension to the upper genital tract predisposing to abscess formation in endometriomas. Therefore, aggressive treatment of BV in patients with known advanced-stage endometriosis may be considered to prevent superinfected endometriomas.

Angiogenic effects of norplant contraception on endometrial histology and uterine bleeding.

Norplant, a sc contraceptive device, releases levonorgestrel in a sustained fashion. Its effectiveness is offset by irregular bleeding patterns. Because vascular endothelial growth factor (VEGF) is stimulated by synthetic progestogens in vitro and in vivo, we postulated that correlations between this angiogenic factor and uterine bleeding patterns might exist. Twenty-eight women who were exposed to Norplant and 13 control women were prospectively followed for 6-8 months. Bleeding diaries were collected, hysteroscopies were performed, endometrial biopsies were obtained for standardized histological evaluation, and VEGF histochemical immunostaining (H)-scores were assigned. Cluster determination-34 (CD34) staining was also performed to quantify the number of endometrial blood vessels per high-power field. Irregular uterine bleeding was common among women using Norplant devices. Endometrial VEGF H-scores were greater in women using Norplant than in control women. New findings of this study show that vessel density did not correlate with epithelial VEGF H-scores but was highly associated with the intensity of stromal and perivascular VEGF. VEGF expression in the latter regions correlated significantly with hysteroscopic abnormalities and irregular bleeding. The expression of this angiogenic protein, particularly in the stromal and perivascular compartments, correlated with microvascular density, hysteroscopically documented hypervascularity, and uterine bleeding profiles. Irregular bleeding with Norplant use appears to reflect paracrine-mediated effects on vascular function by angiogenic factors, such as VEGF.

Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis.

OBJECTIVE: To determine the effects of a thiazolidinedione, ciglitazone, in a rat model of endometriosis. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Experimental surgery laboratory in a university department. ANIMAL(S): Twenty female Sprague-Dawley rats given endometriotic lesions by transplanting autologous uterine tissue to ectopic sites on the peritoneum. INTERVENTION(S): Four weeks after surgery, 20 rats were randomly divided into two groups and treated with IP injections of vehicle every other day (control; n = 10) or ciglitazone (1 mg per rat; n = 10) and euthanized 4 weeks from the start of treatment. MAIN OUTCOME MEASURE(S): At the end of treatment, laparotomy was performed to photograph each explant and then they were measured and weighed. Histologic analysis was performed on the uterine allograft, ovary, and eutopic uterine tissue. RESULT(S): By histologic assessment, both groups maintained folliculogenesis and normal eutopic endometrial architecture. Treatment with ciglitazone significantly decreased the size of ectopic uterine tissues and the mean explant wet weight. The ciglitazone-treated group showed marked epithelial regression compared with the control group. CONCLUSION(S): We conclude that a PPAR-gamma ligand, ciglitazone, reduced the size of experimental endometriosis in the rat model of endometriosis. This animal model suggests that a thiazolidinedione drug may be helpful in women with endometriosis.

Peritoneal macrophages induce RANTES (regulated on activation, normal T cell expressed and secreted) chemokine gene transcription in endometrial stromal cells.

Peritoneal fluid macrophages (PFM) are activated in women with endometriosis, in whom they are thought to mediate or exacerbate inflammation. The effect of PFM on endometrial stromal cells (ESC) was studied using a coculture model to evaluate the influence of IL-1 beta and other macrophage-derived cytokines on the transcriptional activation of the human RANTES (regulated on activation, normal T cell expressed and secreted) gene. Normal endometrial biopsies from four patients were used to prepare stromal cell cultures, and pelvic fluid was collected to isolate peritoneal macrophages. A full length (-940 bp) human RANTES promoter construct provided an indicator of transcriptional activation in luciferase reporter transfection assays. Without lipopolysaccharide (LPS), cocultures with PFM had no effect on ESC RANTES gene expression. However, when PFM were treated with LPS within the coculture apparati, ESC RANTES promoter activity was increased more than 2-fold (P < 0.05). The addition of IL-1 receptor antagonist abrogated activation of the RANTES luciferase transgene by LPS-induced PFM products (P < 0.05). We identified IL-1 from PFM as a major stimulus to initiate ESC RANTES gene expression in cocultures. We postulate that PFM stimulation of RANTES production by ESC could lead to a self-propagating recruitment of inflammatory cells that contribute to the development and progression of endometriotic lesions.