Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

Laparoscopic oocyte retrieval for fertility preservation in a patient with squamous cell carcinoma of the vagina.

OBJECTIVE: To describe a feasible fertility preservation strategy in a woman with vaginal carcinoma. DESIGN: Video case report demonstrating the diagnostic work-up and laparoscopic oocyte retrieval performed under regional anesthesia. SETTING: University tertiary care hospital. PATIENT(S): A 35-year-old nulliparous woman presented with vaginal bleeding and foul-smelling vaginal discharge. After a comprehensive diagnostic work-up, a final diagnosis of squamous cell carcinoma of the vagina stage II (Federation International Obstetrics and Gynecology classification) was made. As per the patient's desire, before undergoing chemoradiotherapy, the patient underwent oocyte cryopreservation. Transvaginal retrieval of oocytes was not feasible because of stenosis of the vaginal introitus and the potential risk of intracavitary tumor cell spillage. Transabdominal ultrasound-guided oocyte retrieval was not possible because of the body's habitus. INTERVENTION(S): The patient underwent ovarian stimulation for in vitro fertilization. To minimize estrogen levels, letrozole was used during controlled ovarian stimulation. Laparoscopic oocyte retrieval was performed under spinal anesthesia. MAIN OUTCOME MEASURE(S): Successful laparoscopic egg retrieval and cryopreservation in a woman with squamous cell carcinoma of the vagina. RESULT(S): A total follicular count of nine was estimated before the oocyte retrieval. Eight oocytes were retrieved at laparoscopy, and eight mature oocytes were successfully cryopreserved. No complications were encountered, and the patient was discharged on the same day of surgery. CONCLUSION(S): To our knowledge, this is the first published case of fertility preservation using the laparoscopic approach in a patient with vaginal cancer. Letrozole is a valuable strategy to reduce high estrogen in patients with gynecological cancer undergoing controlled ovarian stimulation. Laparoscopy oocyte retrieval, performed under regional anesthesia, can be performed in an ambulatory setting and should be considered an effective fertility preservation strategy in patients with large vaginal tumors.

Myomectomy in infertile women: More harm than good?

Adhesion formation following gynecological surgery remains a challenge. The adoption of minimally invasive surgical approaches, such as conventional or robotic-assisted laparoscopy combined with meticulous microsurgical principles and the application of adhesion-reducing substances, is able to reduce the risk of de novo adhesion formation but do not eliminate it entirely. Myomectomy is the most adhesiogenic surgical procedure and postoperative adhesions can have a significant impact on the ability to conceive. Therefore, when surgery is performed as infertility treatment, attention should be paid to whether the benefits outweigh the risks. Among several factors, the size and the location of fibroids are the most accountable factors in terms of adhesion development and post surgical infertility; therefore, the search for effective strategies against adhesion formation in this setting is of paramount importance. The purpose of this review is to evaluate the incidence and factors of adhesion formation and the best preventive measures current available.

Trends in Caesarean Section Rate According to Robson Group Classification among Pregnant Women with SARS-CoV-2 Infection: A Single-Center Large Cohort Study in Italy.

BACKGROUND: Since there is no available data on temporal trends of caesarean section (CS) rates in pregnant women with COVID-19 through the pandemic, we aimed to analyze the trends in caesarean section rate in a large cohort of pregnant women with COVID-19, according to the Robson Ten Group Classification System of deliveries. METHODS: We prospectively enrolled pregnant women with a diagnosis of COVID-19 who delivered in our center between March 2020 and November 2021. Deliveries were classified, according to the Robson group classification, and according to three time periods: (1) deliveries from March 2020 to December 2020; (2) deliveries from January 2021 to April 2021; (3) deliveries from May 2021 to November 2021. We compared pregnancy characteristics and incidence of caesarean section, according to the Robson category in the total population, and according to the three time periods. RESULTS: We included 457 patients matching the inclusion criteria in our analysis. We found that overall CS rate significantly decreased over time from period 1 to period 3 (152/222, 68.5% vs. 81/134, 60.4% vs. 58/101, 57.4%, χ2 = 4.261, p = 0.039). CS rate significantly decreased over time in Robson category 1 (48/80, 60% vs. 27/47,57.4% vs. 8/24, 33.3%, χ2 = 4.097, p = 0.043) and Robson category 3 (13/42, 31% vs. 6/33, 18.2% vs. 2/22, 9.1%, χ2 = 4.335, p = 0.037). We also found that the incidence of induction of labor significantly increased over time (8/222, 3.6% vs. 12/134, 9% vs. 11/101, 10.9%, χ2 = 7.245, p = 0.027). CONCLUSION: Our data provide an overview of the temporal changes in the management and obstetric outcome of COVID-19 pregnant women through the pandemic, confirming that standards of obstetrical assistance for pregnancies complicated by SARS-CoV-2 infection improved over time.

Fertility-Sparing Approach in Patients with Endometrioid Endometrial Cancer Grade 2 Stage IA (FIGO): A Qualitative Systematic Review.

Background: Endometrial cancer (EC) is one of the most common gynecologic malignancy, mostly in postmenopausal women. The gold standard treatment for EC is surgery, but in the early stages, it is possible to opt for conservative treatment. In the last decade, different clinical and pathological markers have been studied to identify women who respond to conservative treatment. A lot of immunohistochemical markers have been evaluated to predict response to progestin treatment, even if their usefulness is still unclear; the prognosis of this neoplasm depends on tumor stage, and a specific therapeutic protocol is set according to the stage of the disease. Objective: (1) To provide an overview of the conservative management of Stage 1A Grade (G) 2 endometrioid EC (FIGO) and the oncological and reproductive outcomes related; (2) to describe the molecular alterations before and after progestin therapy in patients undergoing conservative treatment. Materials and Methods: A systematic computerized search of the literature was performed in the main electronic databases (MEDLINE, Embase, Web of Science, PubMed, and Cochrane Library), from 2010 to September 2021, in order to evaluate the oncological and reproductive outcomes in patients with G2 stage IA EC who ask for fertility-sparing treatment. The expression of several immunohistochemical markers was evaluated in pretreatment phase and during the follow-up in relation to response to hormonal therapy. Only scientific publications in English were included. The risk of bias assessment was performed. Review authors' judgments were categorized as "low risk," "high risk," or "unclear risk" of bias. Results: Twelve articles were included in the study: 7 observational studies and 5 case series/reports. Eighty-four patients who took progestins (megestrol acetate, medroxyprogesterone acetate, and/or levonorgestrel-releasing intrauterine devices) were analyzed. The publication bias analysis turned out to be "low." 54/84 patients had a complete response, 23/84 patients underwent radical surgery, and 20/84 had a relapse after conservative treatment. Twenty-two patients had a pregnancy. The length of follow-up was variable, from 6 to 142 months according to the different studies analyzed. Several clinical and pathological markers have been studied to identify women who do not respond to conservative treatment: PR and ER were the most studied predictive markers, in particular PR appeared as the most promising; MMR, SPAG9, Ki67, and Nrf2-survivin pathway provided good results with a significant association with a good response to progestin therapy. However, no reliable predictive markers are currently available to be used in clinical practice. Conclusions: The conservative treatment may be an option for patients with stage IA G2 EEC who desire to preserve their fertility. The immunohistochemical markers evaluation looks promising in predicting response to conservative treatment. Further large series and randomized clinical trials are needed to confirm these results.

The challenging management of borderline ovarian tumors (BOTs) in women of childbearing age.

Borderline ovarian tumors (BOTs) account for approximately 15% of all epithelial ovarian cancers. In 80% of cases the diagnosis of BOTs is done at stage I and more than a third of BOTs occurs in women younger than 40 years of age wishing to preserve their childbearing potential; the issue of conservative surgical management (fertility-sparing treatment) is thus becoming of paramount importance. At early stages, the modalities of conservative treatment could range from mono-lateral cystectomy to bilateral salpingo-oophorectomy. Although cystectomy is the preferred method to promote fertility it can lead to an elevated risk of recurrence; therefore, an appropriate counseling about the risk of relapse is mandatory before opting for this treatment. Nevertheless, relapses are often benign and can be treated by repeated conservative surgery. Besides the stage of the disease, histological subtype is another essential factor when considering the proper procedure: as most mucinous BOTs (mBOTs) are more commonly unilateral, the risk of an invasive recurrence seems to be higher, compared to serous histotype, therefore unilateral salpingo-oophorectomy is recommended. In the appraisal of current literature, this review aims to gain better insight on the current recommendations to identify the right balance between an accurate staging and an optimal fertility outcome.

Ovarian Drilling: Back to the Future.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The complex metabolic dysregulation at the base of this syndrome often renders infertility management challenging. Many pharmacological strategies have been applied for the induction of ovulation with a non-negligible rate of severe complications such as ovarian hyperstimulation syndrome and multiple pregnancies. Ovarian drilling (OD) is currently being adopted as a second-line treatment, to be performed in case of medical therapy. Laparoscopic ovarian drilling (LOD), the contemporary version of ovarian wedge resection, is considered effective for gonadotropins in terms of live birth rates, but without the risks of iatrogenic complications in gonadotropin therapy. Its endocrinal effects are longer lasting and, after the accomplishment of this procedure, ovarian responsiveness to successive ovulation induction agents is enhanced. Traditional LOD, however, is burdened by the potential risks of iatrogenic adhesions and decreased ovarian reserve and, therefore, should only be considered in selected cases. To overcome these limits, novel tailored and mini-invasive approaches, which are still waiting for wide acceptance, have been introduced, although their role is still not well-clarified and none of them have provided enough evidence in terms of efficacy and safety.

Bleeding epulis gravidarum: what to evaluate?

INTRODUCTION: Hormonal changes during pregnancy may induce modifications in oral mucosa. Epulis gravidarum (EG) is an oral disease arising during pregnancy, usually regressing after delivery. A case of EG managed at our department is described and those previously reported in literature are reviewed in order to define EG clinical features for stratifying the risk of complications and the need of surgery during pregnancy as well as which factors should be considered more relevant in EG management. EVIDENCE ACQUISITION: Electronic databases (Medline, Embase, Web of Sciences, Scopus and Cochrane Library) were searched from inception of each databases until May 2021 to identify clinical studies on management of EG diagnosed during pregnancy. The aim of this review was to identify factors influencing the need and timing of surgical management. EVIDENCE SYNTHESIS: A woman with a triplet pregnancy suffering from EG, complicated by profuse bleeding, required Caesarean section (CS) given the triplet pregnancy and the impending preterm labor. The surgical removal of EG was not performed because it spontaneously regressed without consequences 40 days after delivery. Review analysis indicated that EG clinical management is dependent on types of symptoms and their severity. Multilinear regression analysis showed that operative management strategy was associated with bone loss on X-ray (t=4.23, P=0.003), while EG surgical treatment during pregnancy was associated with pain (t=-2.91, P=0.03). No significant differences were found in management strategy, according to pain (P=0.12), interference with mastication (P=0.98) and speech (P=0.36). A poor oral hygiene was described in 71% of patients as hypothetical trigger. CONCLUSIONS: EG management strategy depends on bleeding, pain and bone loss on X-ray. A multidisciplinary approach is useful to perform a rapid and appropriate diagnosis and to better evaluate pros and cons of surgery during pregnancy and following management.

The negative impact of most relevant infections on fertility and assisted reproduction technology.

Infections may act with variable impact on the physiopathology of the reproductive organs, determining infertility or reducing the outcomes of assisted reproduction technology. The aim of this narrative review is to describe the existing evidence regarding the pathogens with a supposed or recognized role in reproductive medicine. Viral hepatitis, as well as HIV, can reduce sperm quality. Syphilis carries a risk of erectile dysfunction and increased endometrial thickness. Chlamydia is the main cause of pelvic inflammatory disease. In relation to Mycoplasma and Ureaplasma spp., only few species seem to show a correlation with infertility and poor in-vitro fertilization outcomes. There is evidence of a role for bacterial vaginosis in early pregnancy loss. HPV infection in males seems to determine infertility. Herpesviruses are more a risk for fetuses than for fertility itself. Zika virus is responsible for altered early embryo development and waiting to conceive is recommended in suspected or confirmed cases. The impact of SARS-CoV-2 is yet to be elucidated. Rubella and toxoplasmosis can provoke important congenital defects and therefore screening is mandatory before conception; a vaccine for Rubella is recommended. Further and well-designed studies are still needed to better elucidate the role of some infectious agents, to improve fertility and its treatments.

Microbiome and PCOS: State-of-Art and Future Aspects.

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease. The hypothesis that alterations in the microbiome are involved in the genesis of PCOS has been postulated. Aim of this review is to summarize the available literature data about the relationship between microbiome and PCOS. A search on PubMed and Medline databases was performed from inception to November 20Most of evidence has focused on the connection of intestinal bacteria with sex hormones and insulin-resistance: while in the first case, a relationship with hyperandrogenism has been described, although it is still unclear, in the second one, chronic low-grade inflammation by activating the immune system, with increased production of proinflammatory cytokines which interfere with insulin receptor function, causing IR (Insulin Resistance)/hyperinsulinemia has been described, as well as the role of gastrointestinal hormones like Ghrelin and peptide YY (PYY), bile acids, interleukin-22 and Bacteroides vulgatus have been highlighted. The lower genital tract microbiome would be affected by changes in PCOS patients too. The therapeutic opportunities include probiotic, prebiotics and synbiotics, as well as fecal microbiota transplantation and the use of IL-22, to date only in animal models, as a possible future drug. Current evidence has shown the involvement of the gut microbiome in PCOS, seen how humanized mice receiving a fecal transplant from women with PCOS develop ovarian dysfunction, immune changes and insulin resistance and how it is capable of disrupting the secondary bile acid biosynthesis. A future therapeutic approach for PCOS may involve the human administration of IL-22 and bile acid glycodeoxycholic acid.

Fractional Microablative CO2 Laser-Related Histological Changes on Vulvar Tissue in Patients With Genitourinary Syndrome of Menopause.

BACKGROUND AND OBJECTIVES: Fractional CO2 laser has been proposed as an effective treatment for the genitourinary syndrome of menopause (GSM). However, the effects of laser treatment on vulvar tissue have never been assessed. We aimed to assess histological changes related to fractional CO2 laser in vulvar tissue from GSM patients. STUDY DESIGN/MATERIALS AND METHODS: A single-center observational prospective cohort study was performed enrolling all GSM patients from July 2017 to October 2018. Patients underwent three outpatient vulvovaginal applications of fractional CO2 laser and vulvar biopsy before and after treatment. Rates of histological changes in vulvar tissue, the difference in means of Vulva Health Index (VuHI), Vaginal Health Index (VHI), Visual Analogue Scale scores for GSM symptoms, and procedure-related pain, and rate of patient's overall satisfaction with treatment were assessed. Univariate comparisons between continuous variables were performed by using the paired t-test (α error = 0.05). RESULTS: Of 20 enrolled patients, 18 underwent all laser applications, and 15 underwent both vulvar biopsies. 93.3% of patients showed remodeling of vulvar connective tissue; 80% showed improvement in vulvar epithelium trophism and 86.7% showed neovascularization. Differences in means between before and after treatment were significant for VuHI, VHI, and all GSM symptoms. Means ± standard deviation of the degree of pain at each laser application were 4.4 ± 0.9, 3.7 ± 1.6, and 2.9 ± 1.9. The rate of overall satisfaction with the treatment was 72.2%. CONCLUSIONS: Fractional CO2 laser leads to a restoration of the normal architecture of vulvar tissue, with significant improvement in GSM-related signs and symptoms, and overall satisfaction with the treatment in most GSM patients. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Bisphenol A-Induced Epigenetic Changes and Its Effects on the Male Reproductive System.

Bisphenol A (BPA) is a widespread chemical agent which can exert detrimental effects on the male reproductive system. Exposure to BPA has been shown to induce several epigenetic modifications in both animal and human cells. Specifically, BPA could not only modify the methylation pattern of multiple genes encoding proteins related to reproductive physiology but also directly influence the genes responsible for DNA methylation. BPA effects include hormonal alterations, microscopic and macroscopic alteration of male reproductive organs, and inheritable epigenetic changes involving human reproduction. BPA exposure was also linked to prostate cancer. This review aims to show the current scenario of BPA-induced epigenetic changes and its effects on the male reproductive system. Possible strategies to counter the toxic effect of BPA were also addressed.

Effect of rescue fractional microablative CO2 laser on symptoms and sexual dysfunction in women affected by vulvar lichen sclerosus resistant to long-term use of topic corticosteroid: a prospective longitudinal study.

OBJECTIVE: The objective of this study was to evaluate the efficacy of rescue fractional microablative CO2 laser treatment in women with severe symptoms and sexual dysfunction related to lichen sclerosus not responsive to long-term ultra-potent topical corticosteroid treatment. METHODS: Consecutive eligible women with lichen sclerosus referred to our unit who received fractional microablative CO2 laser treatment after failure of ultra-potent topical corticosteroid treatment were enrolled in the study. The diagnosis was confirmed by histological assessment in all cases. Patients underwent two cycles of CO2 laser every 30 to 40 days. The severity of lichen sclerosus-related symptoms, sexual function, and procedure discomfort were evaluated with a visual analog scale in the same individual at baseline, after completion of each treatment cycle. Follow-up visits were scheduled during each treatment cycle and at least 1 month after completion of the treatment. The Friedman ANOVA test was used to evaluate differences in the visual analog scale scores of each symptom during treatment. RESULTS: A total of 100 patients with vulvar lichen sclerosus were screened, 40 of whom fulfilled the eligibility criteria. We found a significant improvement in vulvar itching (χ [2] = 31,182, P < 0.001), vulvar dryness (χ [2] = 40,364, P < 0.001), superficial dyspareunia (χ [2] = 37,488, P < 0.001), and sensitivity during intercourse (χ [2] = 22,143, P < 0.001) after two CO2 laser cycles. Pain related to probe movement and laser application was low and did not change significantly consequent to treatment. No systemic or local adverse effects occurred during or after laser treatment. CONCLUSION: Fractional microablative CO2 laser treatment is safe and might represent an effective rescue procedure for patients suffering from lichen sclerosus who fail to respond to long-term ultra-potent topical corticosteroid treatment. These preliminary findings require further study with adequately powered randomized controlled trials.