Chahin Achtari

The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis

OBJECTIVE To analyze the expression of estrogen receptors α and β as well as their target genes implicated in proliferation, c-myc, cyclin D1, and GREB1, in the endometrium of women with or without endometriosis. DESIGN Expression analysis in human tissue. SETTING University hospitals and a clinic. PATIENT(S) Ninety-one premenopausal women (59 patients with endometriosis and 32 controls) undergoing laparoscopic surgery. INTERVENTION(S) Biopsies were obtained at time of surgery, performed during the proliferative phase of the cycle. MAIN OUTCOME MEASURE(S) Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Tissue localization of these estrogen-regulated genes was analyzed by immunohistochemistry. RESULT(S) Estrogen receptors α and β as well as c-myc, cyclin D1, and GREB1 mRNA expression levels were increased in ectopic tissue in comparison with both normal and eutopic endometrium. Estrogen receptor mRNA levels also were upregulated in the eutopic peritoneal tissue of patients with endometriosis. Cyclin D1 and GREB1 expression was augmented in eutopic endometrium. c-myc, cyclin D1, and GREB1 proteins exhibited a nuclear localization in ectopic endometrial tissue. CONCLUSION(S) This constitutes the first report of increased expression of GREB1, as well as cyclin D1 and c-myc, in peritoneal endometriotic lesions, implicating these proteins in estrogen-dependent growth in this context.

Lipoxin A4 is a novel estrogen receptor modulator

Inflammation is intimately linked with naturally occurring remodeling events in the endometrium. Lipoxins comprise a group of short‐lived, non‐classic eicosanoids possessing potent anti‐inflammatory and proresolution properties. In the present study, we investigated the role of lipoxin A4 (LXA4) in the endometrium and demonstrated that 15‐LOX‐2, an enzyme necessary for LX biosynthesis, is expressed in this tissue. Our results establish that LXA4 possesses robust estrogenic activity through its capacity to alter ERE transcriptional activity, as well as expression of estrogen‐regulated genes, alkaline phosphatase activity, and proliferation in human endometrial epithelial cells. Interestingly, LXA4 also demonstrated antiestrogenic potential, significantly attenuating E2‐induced activity. This estrogenic activity was directly mediated through estrogen receptors (ERs). Subsequent investigations determined that the actions of LXA4 are exclusively mediated through ERα and closely mimic those of the potent estrogen 17β‐estradiol (E2). In binding assays, LXA4 competed with E2 for ER binding, with an IC50 of 46 nM. Furthermore, LXA4 exhibited estrogenic activity in vivo, increasing uterine wet weight and modulating E2‐regulated gene expression. These findings reveal a previously unappreciated facet of LXA4 bioactions, implicating this lipid mediator in novel immunoendocrine crosstalk mechanisms.—Russell R., Gori, I., Pellegrini, C., Kumar, R., Achtari, C., Canny, G. O. Lipoxin A4 is a novel estrogen receptor modulator. FASEB J. 25, 4326–4337 (2011). www.fasebj.org

Augmented epithelial multidrug resistance–associated protein 4 expression in peritoneal endometriosis: regulation by lipoxin A4

OBJECTIVE To compare the expression of the prostaglandin (PG) E(2) transporter multidrug resistance-associated protein 4 (MRP4) in eutopic and ectopic endometrial tissue from endometriosis patients with that of control subjects and to examine whether MRP4 is regulated by the antiinflammatory lipid lipoxin A(4) (LXA(4)) in endometriotic epithelial cells. DESIGN Molecular analysis in human samples and a cell line. SETTING Two university hospitals and a private clinic. PATIENT(S) A total of 59 endometriosis patients and 32 age- and body mass index-matched control subjects undergoing laparoscopy or hysterectomy. INTERVENTION(S) Normal, eutopic, and ectopic endometrial biopsies as well as peritoneal fluid were obtained during surgery performed during the proliferative phase of the menstrual cycle. 12Z endometriotic epithelial cells were used for in vitro mechanistic studies. MAIN OUTCOME MEASURE(S) Tissue MRP4 mRNA levels were quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and localization was analyzed with the use of immunohistochemistry. Cellular MRP4 mRNA and protein were quantified by qRT-PCR and Western blot, respectively. PGE(2) was measured in peritoneal fluid and cell supernatants using an enzyme immunoassay (EIA). RESULT(S) MRP4 was expressed in eutopic and ectopic endometrium, where it was overexpressed in peritoneal lesions and localized in the cytoplasm of glandular epithelial cells. LXA(4) attenuated MRP4 mRNA and protein levels in endometriotic epithelial cells in a dose-dependent manner, while not affecting the expression of enzymes involved in PGE(2) metabolism. Investigations employing receptor antagonists and small interfering RNA revealed that this occurred through estrogen receptor α. Accordingly, LXA(4) treatment inhibited extracellular PGE(2) release. CONCLUSION(S) We report for the first time that MRP4 is expressed in human endometrium, elevated in peritoneal endometriosis, and modulated by LXA(4) in endometriotic epithelial cells.

Compartmentalized secretory leukocyte protease inhibitor expression and hormone responses along the reproductive tract of postmenopausal women

Immunity and hormonal responses in the reproductive tissues of postmenopausal women are poorly understood. Secretory leukocyte protease inhibitor (SLPI), a multifunctional antimicrobial protein expressed at mucosal surfaces, is thought to play a key role in infectious and inflammatory contexts. The aim of this study was to measure SLPI production along the female reproductive tract in postmenopausal women with and without hormonal treatment. We additionally quantified estrogen receptor alpha (ERα) and progesterone receptor A (PRA) in these tissues. Expression of SLPI was decreased in the vagina and ectocervix of women under hormonal treatment. Endocervical ERα mRNA expression was increased while this did not reach significance at the protein level. SLPI expression in the endometrium was not influenced by hormonal treatment. We observed attenuated ERα expression in the cervix and endometrium of hormonally treated women, whereas vaginal expression was increased. PRA expression was augmented in the cervix and endometrium and unchanged in the vagina. Taken together, our results indicate that hormonal responses and receptor expression are differentially regulated in vaginal tissue compared with the cervix and endometrium.

Human papillomavirus (HPV) contamination of gynaecological equipment

Objective The gynaecological environment can become contaminated by human papillomavirus (HPV) from healthcare workers’ hands and gloves. This study aimed to assess the presence of HPV on frequently used equipment in gynaecological practice. Methods In this cross-sectional study, 179 samples were taken from fomites (glove box, lamp of a gynaecological chair, gel tubes for ultrasound, colposcope and speculum) in two university hospitals and in four gynaecological private practices. Samples were collected with phosphate-buffered saline-humidified polyester swabs according to a standardised pattern, and conducted twice per day for 2 days. The samples were analysed by a semiquantitative real-time PCR. Statistical analysis was performed using Pearsons χ2 test and multivariate regression analysis. Results Thirty-two (18%) HPV-positive samples were found. When centres were compared, there was a higher risk of HPV contamination in gynaecological private practices compared with hospitals (OR 2.69, 95% CI 1.06 to 6.86). Overall, there was no difference in the risk of contamination with respect to the time of day (OR 1.79, 95% CI 0.68 to 4.69). When objects were compared, the colposcope had the highest risk of contamination (OR 3.02, 95% CI 0.86 to 10.57). Conclusions Gynaecological equipment and surfaces are contaminated by HPV despite routine cleaning. While there is no evidence that contaminated surfaces carry infectious viruses, our results demonstrate the need for strategies to prevent HPV contamination. These strategies, based on health providers’ education, should lead to well-established cleaning protocols, adapted to gynaecological rooms, aimed at eliminating HPV material.

An unusual uterine tumor with signet ring cell features.

In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology.

Counseling after perineal laceration: does it improve functional outcome?

Introduction and hypothesisSince 2006, the Lausanne University Hospital (CHUV) has offered a 12-week post-partum perineum consultation for patients with third-/fourth-degree tears, providing advice for future deliveries. This study consisted of a retrospective follow-up of these patients, focused on subsequent deliveries and current urinary and anorectal incontinence symptoms.MethodsPatients meeting eligibility criteria were invited to complete a questionnaire on their deliveries, along with validated questionnaires grading urinary (UDI-6 and IIQ-7) and anorectal (Wexner-Vaizey score) incontinence.ResultsSixty-two percent of third-/fourth-degree tears occurred following operative vaginal deliveries. Of 160 participants, 45.6% did not redeliver, 5.6% of whom felt traumatized by their first delivery and reluctant to have another children; 33.2% had a second vaginal delivery, 19.4% had a cesarean section (CS), and 1.2% had both vaginal and CS deliveries; 28% of the CS were not medically indicated. The recurrence rate of third-/fourth-degree tears for subsequent vaginal deliveries was 3.6%.Most patients were mildly or not affected by incontinence symptoms. Symptomatic patients reported urinary incontinence during physical activity and gas leakages; 50–60% saw no change of symptoms since the consultation, 30–40% reported partial or complete recovery. Patients redelivering by CS reported significantly less urinary incontinence (p = 0.046) and less anorectal incontinence (p = 0.069).ConclusionAnal sphincter laceration is associated with urinary and anorectal incontinence, but symptoms improve or disappear in most cases and are globally not invalidating. Perineal physiotherapy seems to contribute to this positive evolution. Fertility rate among these patients is unaffected, but the CS rate is higher than average. Further consideration of sexual and emotional sequelae could improve our current service.

Pregnancy- and Delivery-Associated Colorectal and Proctological Disorders

Normal colorectal physiological function changes during pregnancy. These modifications are generally minor, not serious, and well tolerated by pregnant women. Constipation is the most common problem experienced by pregnant women. Whilst constipation rarely disturbs the course of pregnancy, serious acute colorectal emergencies can sometimes be encountered and should be quickly diagnosed by the colorectal surgeon. Appendicitis is the most common “colorectal” complication seen during pregnancy: to make the diagnosis, it is important to have a high index of suspicion. Specific colorectal inflammatory diseases are generally thought to remain stable during pregnancy, but some larger studies are less optimistic. Distal venous hypertension in the anorectal venous system due to the enlarged uterus is seen frequently and may magnify local “complications.” Hemorrhoids, for example may present with acute thrombotic complications or an anal fissure.

Gynecological Problems Relevant to Coloproctology

During the embryonic period the urorectal septum divides the cloaca into an anterior urogenital sinus, which will eventually become the bladder and urethra, and a posterior anorectum. Pelvic organs therefore share a common origin and assume a similar role: as a reservoir allowing storage and the timely evacuation of urine or feces, thus maintaining continence. Pelvic organs also have a common support complex, the pelvic floor, which is made of muscles and fasciae. The pelvic organ physiology and nerve supply are also very similar. In women, the middle compartment is occupied by the vagina and uterus, the former contributing to pelvic organ support through its close connections to the pelvic sidewalls. Not surprisingly, functional and anatomical dysfunction of the different pelvic compartments frequently coexist. Urinary incontinence (UI) is present in 10–40% of patients consulting for fecal incontinence [14], and symptoms of anorectal incontinence are present in one-third of women consulting for UI. Pelvic organ prolapse also interferes with function by impairing either evacuation or continence. It is therefore of paramount importance for all specialists dealing with pelvic floor dysfunction to be aware of coexisting troubles in other pelvic compartments.