Does Gonadotropin-Releasing Hormone Agonist Administration Before Assisted Reproduction Techniques Improve Pregnancy Rates in Women With Endometriosis?

Importance: Axial downregulation with a 3- to 6-month administration of gonadotropin-releasing hormone agonists (GnRH-a) prior to assisted reproduction techniques has been proposed in order to improve clinical pregnancy rates in women with endometriosis. Although reduced inflammation, improved oocyte quality, and restored endometrial receptivity have been postulated, further investigation of their actual benefit and mechanism of action is considered essential. In that direction, well-designed clinical trials regarding the role of GnRH-a in IVF are necessary. Objective: The purpose of this review is to clarify whether GnRH-a administration prior to IVF-FET procedures improves pregnancy rates in women with endometriosis. Evidence Acquisition: A literature review was conducted in MEDLINE (PubMed), Cochrane, and Google Scholar and concluded on September 10, 2022. Results: Two Cochrane meta-analyses and 16 selected studies present various interesting data of assisted reproduction technique procedures on patients with endometriosis-related infertility with or without depot GnRH-a pretreatment. Conclusions: The regimen may have a positive clinical effect on cases of severe endometriosis (American Society for Reproductive Medicine stages III-IV), but their use is not routinely recommended in order to improve pregnancy rates. Relevance: Endometriosis and infertility are closely related through various pathogenetic mechanisms. Endometriosis has been traditionally considered to negatively affect fundamental aspects of the in vitro fertilization-frozen embryo transfer procedure. Numerous interventions, both medical and surgical, have been proposed in order to improve IVF success rates, and the optimal management of these cases poses an ever pressing challenge.

The ErbB Signaling Network and Its Potential Role in Endometrial Cancer.

Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/ß-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.

Comprehensive Analysis of DNA Methyltransferases Expression in Primary and Relapsed Ovarian Carcinoma.

BACKGROUND: Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, its recurrence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with an ominous prognosis and chemotherapy resistance, but the role of DNA methyltransferases (DNMTs) in EOC remains to be investigated. METHODS: In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. RESULTS: Our results showed that the DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and the DNMT2 level was lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage-II to Stage-IV carcinomas. The proteomic data also suggested that the DNMT1 and DNMT3A levels were increased in the tumors. Similarly, the DNMT1, DNMT3A and DNMT3L protein levels were overexpressed and DNMT2 expression was reduced in high-grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. The DNMT3A, DNMT1 and DNMT3B mRNA levels were correlated with overall survival. CONCLUSIONS: Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high-grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights the presumed tumor-suppressor activity of this gene in ovarian carcinoma.

The influence of expanded carrier screening in assisted reproductive techniques: changed the 'game'- review.

Expanded carrier screening constitutes a new scientific tool able to detect conditions that can be treated immediately after birth or during pregnancy. Its implementation could affect both the prenatal period and assisted reproductive techniques. It is strongly beneficial as it provides much useful information to future parents concerning the medical status of their offspring. In addition, the definition of 'serious/severe', regulating preimplantation diagnosis, donor insemination, and even the definitions of prerequisites for abortion diseases, should be reformed including all clinically severe diseases. On the other hand, controversies may arise especially regarding gamete donation. Future parents and offspring maybe informed regarding donors' demographic and medical characteristics. This study aims to investigate the effects of the implementation of expanded carrier screening in the reformation of the definition of 'severe/serious' disease, the decision-making of future parents, gamete donation, and the possible new moral dilemmas that may arise.

Management of pre-, peri-, and post-menopausal abnormal uterine bleeding: When to perform endometrial sampling?

Abnormal uterine bleeding (AUB) is defined as abnormal volume, duration, or frequency of menstrual period and is a common symptom in women of all ages (premenopausal, perimenopausal, and postmenopausal). The acronym PALM-COEIN, introduced by the International Federation of Gynecology and Obstetrics (FIGO), facilitates the evaluation and differential diagnosis of AUB, mostly in premenopausal women with AUB. Endometrial evaluation (including ultrasound or hysteroscopic imaging and tissue sampling) for subtle pathology is proposed in patients who are at high risk for endometrial cancer and in patients at low risk who present with AUB and who present poor correspondence in medical treatment. Many new diagnostic modalities are available in clinicians in order to help the assessment of women presenting with abnormalities in their menstrual pattern. The present study reviews the optimal management of women presenting with AUB, taking into consideration the actual need for invasive management in these women, who of them require it, and who can be diagnosed without histological verification. The importance of endometrial tissue sampling in women who present with AUB as well as the best timing for a clinician to conduct a biopsy are two axons analyzed below, according to the latest worldwide guidelines and major publications about this subject.

DNA Methylation in Epithelial Ovarian Cancer: Current Data and Future Perspectives.

Ovarian cancer is an aggressive disease, and only a few cases are diagnosed at early stages due to the absence of symptoms. Τhe majority of malignant ovarian tumors (>90%) are of epithelial origin and are subdivided into five histological sub types according to different molecular pathogenesis and clinical behavior. High-grade serous ovarian cancer is the most common subtype (70%). However, the different histotypes of ovarian cancer should be viewed as separate diseases both clinically and in biomarker studies. At present, surgical debulking and platinum/taxane - based chemotherapy is the standard of care for epithelial ovarian cancer. Most patients show an initial response to this therapeutic approach, but the majority of them experience disease recurrence at which point cure is no longer possible, due to acquired resistance in those chemotherapeutic regimens. Nevertheless, the current treatment model is still a "one-sizefits- all" approach. Epigenetic modifications represent heritable modifications in gene expression without alteration of the DNA sequence. DNA methylation is the best-studied epigenetic mechanism, and in epithelial ovarian cancer, the methylenome is widely altered. In addition, patterns of DNA methylation may represent potential diagnostic and prognostic markers as well as markers predictive of chemoresistance and potential therapeutic targets. This article systematically reviews the complex area of DNA methylation in ovarian carcinoma and summarizes the current implications and future perspectives of its use as a screening, diagnostic, prognostic and predictive tool as well as in personalized cancer therapy.

Cervical Pathology Following HPV Vaccination in Greece: A 10-year HeCPA Observational Cohort Study.

BACKGROUND: In Greece the population-level impact of HPV vaccination is unknown due to lack of official registries. This study presents in a pragmatic frame the comparison of cervical pathology data between HPV-vaccinated and unvaccinated women referred for colposcopy. PATIENTS AND METHODS: This is an observational prospective cohort study performed in 7 academic Obstetrics and Gynaecology Departments across Greece between 2009-2019. Cases were women that had completed HPV vaccination before coitarche and were referred for colposcopy due to abnormal cytology. For each vaccinated woman an unvaccinated matched control was selected. RESULTS: A total of 849 women who had been vaccinated before coitarche and 849 unvaccinated controls were recruited. The combination of cytological, colposcopic and molecular findings necessitated treatment in only a single case among vaccinated (0.1%) and in 8.4% among unvaccinated. CONCLUSION: HPV vaccination at a proper age can markedly reduce development of severe cervical precancers and consequently the need for treatment, as well as their long-term related obstetrical morbidity.

Expression of phosphorylated Akt, mTOR and MAPK in type I endometrial carcinoma: clinical significance.

BACKGROUND/AIM: The Akt/mTOR and MAPK pathways are frequently activated in various tumor types but data on endometrial carcinoma are limited. The aim of the present study was to investigate the clinical significance of the expression of phosphorylated MAPK, Akt and mTOR (p-MAPK, p-Akt, p-mTOR) in type I endometrial carcinoma. MATERIALS AND METHODS: The study comprised of 103 formalin-fixed paraffin-embedded (FFPE) type I endometrial carcino ma cases, retrospectively retrieved and assessed by immuno histochemistry for p-MAPK, p-Akt and p-mTOR expression. The expression of these proteins was also studied in non-neoplastic endometrial tissue adjacent to the tumor. RESULTS: The expression patterns of these molecules differed between malignant and non-tumorous tissue specimens. The immuno reactivity for p-Akt was exclusively detected in the neoplastic tissues. Expression levels of p-MAPK were higher in tumors compared to non-neoplastic endometrium (p<0.001), while p-mTOR was found to be over-expressed in non-neo plastic endometrium compared to carcinomas (p=0.001). Expression of p-Akt was correlated with p-MAPK protein levels (p=0.022, r=0.229). On the other hand, no association was found with clinicopathological parameters and with disease-free (DFS) or overall survival (OS) of the patients. CONCLUSION: Our findings support the de-regulation of the PI3K/Akt/mTOR and MAPK signaling pathways in type I endometrial carcinomas suggesting involvement of these pivotal pathways in endometrial carcinogenesis.

The prognostic role of preoperative serum CA 125 levels in patients with endometrial carcinoma.

PURPOSE: Previous studies have shown that elevated preoperative serum CA 125 levels strongly correlate with various clinical and pathological variables and prognosis of patients with endometrial carcinoma (EC). The aim of the present study was to evaluate the clinical significance of preoperative serum CA 125 levels in patients with EC. METHODS: A retrospective study of all EC patients treated at our institution between 1995 and 2010 with available follow-up was conducted. The preoperative serum level of CA 125 was measured in 99 patients and evaluated in relation to various clinical and pathological variables and outcome. We used the cut-off level of 20 U/ml for CA 125 on chi-square test for categorical variables. Survival analysis was performed with the use of Kaplan Meier method, the log rank test and Cox proportional hazards regression analysis. RESULTS: In the early stages of disease the mean values of CA 125 were 35 U/ml (SD±70) for stages IA-IB and 21 U/ml (SD±29) for stage IC (Mann-Whitney test for continuous variables). In advanced stages of disease (III-IV), the values of preoperative serum CA 125 levels were statistically increased, with mean value 54 U/ml (SD±44), in comparison to stages IA-IB (p=0.02) and IC (p=0.007). According to the multivariate analysis, elevated preoperative serum CA 125 level (p=0.043) and histological tumor type (p=0.004) were independent prognostic factors for disease free survival (DFS) and overall survival (OS) of patients with EC. CONCLUSION: The current study suggests that measurement of preoperative serum CA 125 is a useful clinical tool in the prognosis of patients with EC.

Expression and potential role of ErbB receptors in type II endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common malignancy of the female genital tract. Based on clinical and pathological features, endometrial cancer is classified into two types. The aim of our study was to describe the expression and the potential clinical role of ErbB receptors in Greek patients with type II endometrial cancer. STUDY DESIGN: Between 1991 and 2008, 10 women with histologically confirmed type II endometrial cancer were referred to the Department of Gynecologic Oncology of the University of Patras Medical School. Tissue specimens from endometrial lesions were immunostained for EGFR, ErbB-2, ErbB-3 and ErbB-4. RESULTS: For EGFR, 5 cases were positive (50%) and 5 cases were negative. For ErbB-2, 9 cases were positive (90%) and 1 case was negative. For ErbB-3, all cases were positive. For ErbB-4, 7 cases were positive (70%) and 3 cases were negative. Also for all ErbB receptors, 5 cases were positive (50%). During follow up, 3 patients died from their disease. All of them had papillary serous endometrial cancer and 2 of them were positive for all ErbB receptors. CONCLUSION: Although our study was based on a small number of cases, it is obvious that we had high expression levels of ErbB receptors in patients with type II endometrial cancer. Also the majority of patients with dismal outcome were positive for all ErbB receptors. This is very important, as ErbB-targeted therapies may be clinically active as adjuvant therapy in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression.

Systemic Sclerosis and Multiple Cancers of the Female Genital Tract: Prolonged Survival following Current Treatment Strategies.

Background. Systemic sclerosis is a rare, chronic, multisystem, and autoimmune disease. There is an overall increased risk of malignancy in patients with systemic sclerosis. However, multiple cancers of the female genital tract in patients with SSc are a very rare event. Our aim is to present a case of SSc and multiple cancers of the female genital tract, with prolonged survival following current treatment strategies. Case. The patient, a 43-year-old nulliparous premenopausal Greek woman suffering from systemic sclerosis, presented with a history of abdominal pain and abnormal uterine bleeding. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, total omentectomy, appendectomy, and pelvic lymph node dissection. The histopathology revealed synchronous primary cancers of the endometrium and left ovary. The final diagnosis was stage Ib endometrial cancer endometrioid type and stage IIIc ovarian cancer endometrioid type. She underwent postoperative adjuvant chemotherapy and remains well without evidence of disease 89 months after initial surgery. Conclusion. Although our patient was diagnosed at advanced stage disease, prolonged survival may be related with radical surgery and postoperative adjuvant chemotherapy according to current treatment strategies.

Percutaneous minimally invasive management of iatrogenic ureteral injuries.

PURPOSE: To present experience with the percutaneous management of iatrogenic ureteral injuries. PATIENTS AND METHODS: Eighteen women and six men with a mean age of 59.3 years (range 33-80 years) received a diagnosis of ureteral injury sustained during gynecologic, urologic, and general surgical procedures. In a total of 25 injured ureters, 12 had interruption of continuity of their lumen, 10 were associated with contrast extravasation, and 3 were related to both. A standard percutaneous nephrostomy tract was established on the side of the afflicted kidney. Combined use of hydrophilic guidewires and balloon dilations were performed to achieve antegrade recanalization of the ureteral lesion. Then, a ureteral stent was inserted to assure patency. RESULTS: Average stricture length was 1.21 (range 0.5-1.9 cm). Success of the aforementioned technique was possible in 18 ureters. Successful management in one session took place in 14 ureters. Average hospitalization time was 1.8 days (range 0-5 d). The follow-up period ranged between 12 and 18 months, with mean follow-up time of 12.9 months. Ureteral patency was evident at 1 week follow-up in six patients with obstructed ureters. In the remaining patients, balloon dilation of the stricture was repeated, and another stent was placed. Extravasation of contrast was observed in two patients with extravasating ureters in the same period. Nephrostomy tubes were removed after a mean indwelling period of 5.9 weeks (range 1-12 wks). Two patients treated by the described method died during their hospitalization in the intensive care unit because of sepsis from peritonitis that was related to colon injury and multiple concomitant injuries. Major complications were not observed in the remaining 22 patients during the follow-up period. CONCLUSION: The minimally invasive management of ureteral injuries is a safe and efficient method for both ureteral obstruction and/or laceration in a wide range of iatrogenic ureteral injuries.

Sarcoidosis of the vulva: a case report.

Sarcoidosis of the vulva is a very rare condition. Until now, only four cases have been reported in English literature. The patient, a 48-year-old, gravid 3, para 2 postmenopausal Greek woman presented with a 6 months history of perineal pain. The patient underwent a wide local excision of the painful lesion. The histology revealed sarcoidosis of the vulva. She remains well without evidence of relapse 12 months after operation.

A prospective randomized study comparing gonadotropin-releasing hormone agonists or gonadotropin-releasing hormone antagonists in couples with unexplained infertility and/or mild oligozoospermia.

OBJECTIVE: To compare the efficacy of GnRH antagonist vs. GnRH agonist administration for controlled ovarian hyperstimulation (COH) in assisted reproduction. DESIGN: A prospective, randomized trial. SETTING: Clinical research unit at a tertiary care medical center. PATIENT(S): Sixty-five patients with unexplained infertility or mild male subfertility undergoing COH for IUI. INTERVENTION(S): Twenty-nine women (group A) were randomized to receive 600 microg of busereline acetate per day starting in the midluteal phase of the cycle (long protocol), whereas 36 women (group B) were treated with 0.25 mg/d of the GnRH antagonist Cetrorelix starting from day 6 of the cycle. The starting dose of recombinant FSH was 150 IU in women of both groups. Insemination was performed 34 hours after hCG injection. MAIN OUTCOME MEASURE(S): Clinical and successful ongoing pregnancy rate (PR), measurements of serum FSH, LH, E2, and P, number of recruited follicles, duration of stimulation period, and amount of gonadotropins used. RESULT(S): Women in group A required significantly more days of treatment (median: 12.0 vs. 9.0) and significantly more total units of recombinant FSH (median 1,800 vs. 1,550) as compared with the corresponding values of the antagonist group (group B). Serum FSH, LH, E2, and P were significantly higher on the antagonist group on days 2 and 6 of stimulation. However, these differences regress until the day of hCG administration. CONCLUSION(S): The GnRH antagonists have facilitated short and simple treatment, and are particularly attractive for administration in women undergoing COH, achieving comparable PR with the long protocol regimen.