NMR Metabolomics of Primary Ovarian Cancer Cells in Comparison to Established Cisplatin-Resistant and -Sensitive Cell Lines.

Cancer cell lines are frequently used in metabolomics, such as in vitro tumor models. In particular, A2780 cells are commonly used as a model for ovarian cancer to evaluate the effects of drug treatment. Here, we compare the NMR metabolomics profiles of A2780 and cisplatin-resistant A2780 cells with those of cells derived from 10 patients with high-grade serous ovarian carcinoma (collected during primary cytoreduction before any chemotherapeutic treatment). Our analysis reveals a substantial similarity among all primary cells but significant differences between them and both A2780 and cisplatin-resistant A2780 cells. Notably, the patient-derived cells are closer to the resistant A2780 cells when considering the exo-metabolome, whereas they are essentially equidistant from A2780 and A2780-resistant cells in terms of the endo-metabolome. This behavior results from dissimilarities in the levels of several metabolites attributable to the differential modulation of underlying biochemical pathways. The patient-derived cells are those with the most pronounced glycolytic phenotype, whereas A2780-resistant cells mainly diverge from the others due to alterations in a few specific metabolites already known as markers of resistance.

Sentinel node mapping in high-intermediate and high-risk endometrial cancer: Analysis of 5-year oncologic outcomes.

OBJECTIVE: To assess 5-year oncologic outcomes of apparent early-stage high-intermediate and high-risk endometrial cancer undergoing sentinel node mapping versus systematic lymphadenectomy. METHODS: This is a multi-institutional retrospective, propensity-matched study evaluating data of high-intermediate and high-risk endometrial cancer (according to ESGO/ESTRO/ESP guidelines) undergoing sentinel node mapping versus systematic pelvic lymphadenectomy (with and without para-aortic lymphadenectomy). Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard methods. RESULTS: Overall, the charts of 242 patients with high-intermediate and high-risk endometrial cancer were retrieved. Data on 73 (30.1%) patients undergoing hysterectomy plus sentinel node mapping were analyzed. Forty-two (57.5%) and 31 (42.5%) patients were classified in the high-intermediate and high-risk groups, respectively. Unilateral sentinel node mapping was achieved in all patients. Bilateral mapping was achieved in 67 (91.7%) patients. Three (4.1%) patients had site-specific lymphadenectomy (two pelvic areas only and one pelvic plus para-aortic area), while adjunctive nodal dissection was omitted in the hemipelvis of the other three (4.1%) patients. Sentinel nodes were detected in the para-aortic area in eight (10.9%) patients. Twenty-four (32.8%) patients were diagnosed with nodal disease. A propensity-score matching was used to compare the aforementioned group of patients undergoing sentinel node mapping with a group of patients undergoing lymphadenectomy. Seventy patient pairs were selected (70 having sentinel node mapping vs. 70 having lymphadenectomy). Patients undergoing sentinel node mapping experienced similar 5-year disease-free survival (HR: 1.233; 95%CI: 0.6217 to 2.444; p = 0.547, log-rank test) and 5-year overall survival (HR: 1.505; 95%CI: 0.6752 to 3.355; p = 0.256, log-rank test) than patients undergoing lymphadenectomy. CONCLUSIONS: Sentinel node mapping does not negatively impact 5-year outcomes of high-intermediate and high-risk endometrial cancer. Further prospective studies are warranted.

Characteristics and outcomes of surgically staged multiple classifier endometrial cancer.

OBJECTIVE: The growing adoption of molecular and genomic characterization is changing the current landscape of treatment of endometrial cancer patients. Using the surrogate molecular classification, endometrial cancer patients can be classified in four subgroups: POLE mutated (POLEmut), MMRd/MSI-H, p53 abnormal (p53abn), and no specific mutational profile (NSMP). However, some patients can harbor two or more molecular features (defined as multiple classifier). Since the rarity of this occurrence, evidence regarding multiple classifiers is still limited. Here, we described characteristics and outcomes of multiple classifiers. METHODS: This is a multi-institutional retrospective study. Data of consecutive patients having 2 or more molecular features were collected. Survival was assessed using the Kaplan-Meier and Cox proportional hazard methods. RESULTS: Charts of 72 multiple classifiers were reviewed. Median (range) follow-up was 9.8 (1.2, 37.5) months. Overall, 31 (43%) patients had POLEmut. Patients with POLEmut-MMRd/MSI-H, POLEmut-p53abn, and POLEmut-MMRd/MSI-H-p53abn were 6 (8.3%), 20 (27.8%), and 5 (6.9%), respectively. Among those 31 patients, no recurrence occurred within a median follow-up of 10.5 months (only seven (22.6%) patients had at least 2-year follow-up). The remaining 41 (56.9%) patients were diagnosed with tumors harboring both p53 and MMRd/MSI-H. Among them, four (9.8%) recurrences occurred at a median follow-up time of 8.9 months. Adjuvant therapy (other than vaginal brachytherapy) was administered in 5/31 (16%) and 25/41 (61%) patients with and without POLEmut, respectively (p < 0.001). CONCLUSIONS: Multiple classifiers endometrial cancer with POLEmut are characterized by good prognosis even in case of presence of MMRd/MSI-H and/or p53abn. Additional studies with long-term follow-up are needed.

HPV-related lesions after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer: A focus on the potential role of vaccination.

OBJECTIVE: To date, no data supports the execution of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia (CIN2+) and early-stage cervical cancer. We aim to evaluate the potential effect of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer. METHODS: This is a multi-center retrospective study evaluating data of women who develop lower genital tract dysplasia (including anal, vulvar and vaginal intra-epithelial neoplasia) after having hysterectomy for CIN2+ and FIGO stage IA1- IB1 cervical cancer. RESULTS: Overall, charts for 77 patients who developed lower genital tract dysplasia were collected. The study population included 62 (80.5%) and 15 (19.5%) patients with CIN2+ and early-stage cervical cancer, respectively. The median (range) time between hysterectomy and diagnosis of develop lower genital tract dysplasia was 38 (range, 14-62) months. HPV types covered by the nonavalent HPV vaccination would potentially cover 94.8% of the development of lower genital tract dysplasia. Restricting the analysis to the 18 patients with available HPV data at the time of hysterectomy, the beneficial effect of nonvalent vaccination was 89%. However, considering that patients with persistent HPV types (with the same HPV types at the time of hysterectomy and who developed lower genital tract dysplasia) would not benefit from vaccination, we estimated the potential protective effect of vaccination to be 67% (12 out of 18 patients; four patients had a persistent infection for the same HPV type(s)). CONCLUSIONS: Our retrospective analysis supported the adoption of HPV vaccination in patients having treatment for HPV-related disease. Even in the absence of the uterine cervix, HPV vaccination would protect against develop lower genital tract dysplasia. Further prospective studies have to confirm our preliminary research.

Recurrence of Uterine Fibroids After Conservative Surgery or Radiological Procedures: a Narrative Review.

The present narrative review aims to discuss the available data on the incidence and the risk factors of uterine fibroids (UFs) recurrence after different types of conservative surgical or radiologic procedures in women wishing to preserve their uterus. UFs are the most common benign tumors in women all over the world. Clinical presentation, including abnormal uterine bleeding (AUB), pelvic pain, bulky symptoms, and infertility affect patients' quality of life, and a large variety of conservative treatments are available especially for those with desire of pregnancy. Fertility sparing surgery, by either laparoscopy, hysteroscopy or laparotomy, or radiological interventions (uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound), are the most common therapeutic approaches. However, the genetic or acquired predisposition to UFs remain despite the treatments, and the recurrences are frequently described in a large percentage of patients. The most relevant risk factors for recurrence of UFs are young age at the first surgery, incomplete fibroid resection, the presence of multiple lesions, an enlarged uterus, and the coexistence with other pelvic diseases. The discussion on the possible medical strategy to reduce the recurrence is an open field of clinical investigation, in particular by using hormonal drugs.

Hysterectomy alone vs. hysterectomy plus sentinel node mapping in endometrial cancer: Perioperative and long-term results from a propensity-score based study.

OBJECTIVE: To compare outcomes after hysterectomy and hysterectomy plus sentinel node mapping (SNM) in endometrial cancer (EC) patients. MATERIALS AND METHODS: This is a retrospective study, collecting data of EC patients treated between 2006 and 2016 in nine referral centers. RESULTS: The study population included 398 (69.5%) and 174 (30.5%) patients having hysterectomy and hysterectomy plus SNM. As the results of the adoption of a propensity-score matched analysis, we selected two homogeneous cohort of patients (150 having hysterectomy only vs. 150 having hysterectomy plus SNM). The SNM group had a longer operative time, but did not correlate with length of hospital stay and estimated blood loss. Overall severe complication rates were similar between groups (0.7% in the hysterectomy group vs. 1.3% in the hysterectomy plus SNM group; p = 0.561). No lymphatic-specific complication occurred. Overall, 12.6% of patients having SNM were diagnosed with disease harboring in their lymph nodes. Adjuvant therapy administration rate was similar between groups. Considering patients having SNM, 4% of patients received adjuvant therapy on the basis of nodal status alone; all the other patients received adjuvant therapy also on the basis of uterine risk factors. Five-year disease-free (p = 0.720) and overall (p = 0.632) survival was not influenced by surgical approach. CONCLUSIONS: Hysterectomy (with or without SNM) is a safe and effective method for managing EC patients. Potentially, these data support the omission of side specific lymphadenectomy in case of unsuccessful mapping. Further evidence is warranted in to confirm the role SNM in the era of molecular/genomic profiling.

Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer.

Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

Evaluating long-term outcomes of three approaches to retroperitoneal staging in endometrial cancer.

OBJECTIVE: Sentinel lymph node mapping (SNM) has gained popularity in managing apparent early-stage endometrial cancer (EC). Here, we evaluated the long-term survival of three different approaches of nodal assessment. METHODS: This is a multi-institutional retrospective study evaluating long-term outcomes of EC patients having nodal assessment between 01/01/2006 and 12/31/2016. In order to reduce possible confounding factors, we applied a propensity-matched algorithm. RESULTS: Overall, 940 patients meeting inclusion criteria were included in the study, of which 174 (18.5%), 187 (19.9%), and 579 (61.6%) underwent SNM, SNM followed by backup lymphadenectomy (LND) and LND alone, respectively. Applying a propensity score matching algorithm (1:1:2) we selected 500 patients, including 125 SNM, 125 SNM/backup LND, and 250 LND. Baseline characteristics of the study population were similar between groups. The prevalence of nodal disease was 14%, 16%, and 12% in patients having SNM, SNM/backup LND and LND, respectively. Overall, 19 (7.6%) patients were diagnosed with low volume nodal disease. The survival analysis comparing the three techniques did not show statistical differences in terms of disease-free (p = 0.750) and overall survival (p = 0.899). Similarly, the type of nodal assessment did not impact survival outcomes after stratification based on uterine risk factors. CONCLUSION: Our study highlighted that SNM provides similar long-term oncologic outcomes than LND.

Does advanced paternal age affect outcomes following assisted reproductive technology? A systematic review and meta-analysis.

Infertility affects more than 14% of couples, 30% being caused by male factor infertility. This meta-analysis includes 28 studies, selected according to PRISMA guidelines. Data were extracted from these studies to collate cycles separating paternal age at 30, 35, 40, 45 and 50 years (±1 year). Primary outcomes of interest were clinical pregnancy, live birth and miscarriage rates. Secondary outcomes were the number of fertilized eggs, cleavage-stage embryos and blastocysts, and embryo quality per cycle. Fixed-effects and random-effects models giving pooled odds ratios (OR) were used to assess the effect of paternal age. This meta-analysis included a total 32,484 cycles from 16 autologous oocyte studies and 12 donor oocyte studies. In autologous cycles, a statistically significant effect of paternal age <40 years was noted in clinical pregnancy (OR 1.65, 95% confidence interval [CI] 1.27-2.15), live birth (OR 2.10, 95% CI 1.25-3.51) and miscarriage (OR 0.74, 95% CI 0.57-0.94) rates. Paternal age <50 years significantly reduced miscarriage rate (OR 0.68, 95% CI 0.54-0.86), and increased blastocyst rate (OR 1.61, 95% CI 1.08-2.38) and number of cleavage-stage embryos (OR 1.67, 95% CI 1.02-2.75) in donor oocyte cycles, where maternal age is controlled. This is an important public and societal health message highlighting the need to also consider paternal age alongside maternal age when planning a family.

Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness.

Auranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well-known inhibition of thioredoxin reductase. Among these targets, inhibitory-κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology-like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation.

Fertility-sparing surgery for women with stage I cervical cancer of 4 cm or larger: a systematic review.

OBJECTIVE: To investigate current evidence on oncological, fertility and obstetric outcomes of patients with stage I cervical cancer of 4 cm or larger undergoing fertility-sparing surgery (FSS). METHODS: Systematic review of studies including women affected by stage I cervical cancer ≥4 cm who underwent FSS. Main outcome measures: disease-free survival (DFS), overall survival (OS), pregnancy rate, live birth rate, premature delivery rate. RESULTS: Fifteen studies met all eligibility criteria for this systematic review, involving 48 patients affected by cervical cancer ≥4 cm who completed FSS. Three patients (6.3%) experienced a recurrence and one of them (2.1%) died of disease. The 5-year DFS rate was 92.4%. The 5-year OS rate was 97.6%. A significantly shorter 5-year DFS was reported for high-risk patients (G3, non-squamous histotype, diameter ≥5 cm) compared with low-risk (74.7% vs. 100%; log-rank test, p=0.024). Data about fertility outcomes were available for 12 patients. Five patients out of 12 (41.7%) attempted to conceive with an estimated pregnancy rate of 80%, a live birth rate of 83.3% and a premature delivery rate of 20%. CONCLUSION: Women with high tumor grade, aggressive histology and tumor size ≥5 cm have a higher risk of recurrence. Oncologic outcomes are encouraging among low-risk patients; however, the lack of high-quality studies makes it difficult to draw any firm conclusions. Prospective multicentric clinical trials with a proper selection of inclusion/exclusion criteria should be conducted in women with low-risk factors, strong desire to preserve their fertility and high likelihood to conceive.

Physical Activity and Female Sexual Dysfunction: A Lot Helps, But Not Too Much.

BACKGROUND: Research on the relationship between physical activity (PA) and female sexual dysfunction (FSD) is lacking. AIM: To investigate the clinical, psychological, and sexual correlates of PA in women with FSD. METHODS: A non-selected series of n = 322 pre- and post-menopausal patients consulting for FSD was retrospectively studied. Regular involvement in PA and its frequency (<1 hour/week: sedentary, 1-3 hours/week: active, 4-6 hours/week: very active, >6 hours/week: extremely active) were investigated with a specific question. OUTCOMES: FSDs, including HSDD (Hypoactive sexual desire disorder) and FGAD (Female genital arousal disorder), were diagnosed according to a structured and clinical interview. Participants underwent a physical examination and a clitoral Doppler ultrasound, and were asked to complete the Female Sexual Function Index, Female Sexual Distress Scale-Revised, Body Uneasiness Test, and Middlesex Hospital Questionnaire. RESULTS: At multivariate analysis, women engaging in PA (67.4%, n = 217) scored significantly higher in several Female Sexual Function Index domains - including desire, arousal and lubrication - and showed lower sexual distress and lower resistance of clitoral arteries, as compared to sedentary women. A significant, inverse association between PA and HSDD was observed. Mediation analysis demonstrated that the negative association between PA and HSDD was partly mediated by body image concerns (Body Uneasiness Test Global severity index), psychopathological symptoms (Middlesex Hospital Questionnaire total score) and sexual distress (Female Sexual Distress Scale-Revised score). These latter 2 factors also partly mediated the association between PA and a reduced risk of FGAD, whilst a lower BMI was a full mediator in the relationship between PA and FGAD. Finally, extreme PA was associated with significantly worse scores in several psychosexual parameters (i,e, sexual satisfaction and histrionic/hysterical symptoms), even compared to a sedentary lifestyle. CLINICAL IMPLICATIONS: Women consulting for FSD may gain benefits on desire, arousal, lubrication and sex-related distress from regular PA; however, physicians should remain alert to the downsides of excessive exercise. STRENGTHS & LIMITATIONS: The main strength lies in the novelty of the findings. The main limitations are the cross-sectional nature, the clinical setting, the small sample size of the different PA groups, and the use of self-reported instruments for the evaluation of PA. CONCLUSION: In women with FSD, PA was associated with better sexual function and clitoral vascularization, lower sexual distress and reduced odds of HSDD and FGAD; the benefits of PA on sexuality were mediated by both psychological and organic determinants; excessive PA was related with a poor overall sexual function and with a low sexual satisfaction. Maseroli E, Rastrelli G, Di Stasi V, et al. Physical Activity and Female Sexual Dysfunction: A Lot Helps, But Not Too Much. J Sex Med 2021;18:1217-1229.

The relation between endometrioma and ovarian cancer.

INTRODUCTION: The relationship between endometrioma and ovarian cancer is a topic of discussion in the field of endometriosis and to date it is still debated whether ovarian endometriosis may represent a risk factor for ovarian cancers. EVIDENCE ACQUISITION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to October 2020. Primary outcome of interest was ovarian cancer incidence in patients with endometriosis. Secondary outcome was ovarian cancer prognosis in patients with endometriosis compared to patient without endometriosis. EVIDENCE SYNTHESIS: Patients with ovarian endometriosis has a slight increase risk of developing ovarian cancer (merely 1.8%), being the general population risk for ovarian cancer 1.31%. In patient at postmenopausal age, long-lasting endometriosis, early-age diagnosis, infertility and/or infertility treatment the risk of developing ovarian cancer is higher. Endometriosis-related ovarian cancers are generally clear cell and endometrioid and are diagnosed at early stage compared to non-endometriosis related ovarian cancer. CONCLUSIONS: The lifetime risk for ovarian cancer is low in endometriosis patients in general and higher in subgroups of patients allowing a tailored management based on patient characteristics. Endometriosis is a chronic disease negatively affecting the quality of life, nonetheless, concerns on ovarian cancer should be avoided in order to reduce the burden of the disease on women's health.

SHBG as a Marker of NAFLD and Metabolic Impairments in Women Referred for Oligomenorrhea and/or Hirsutism and in Women With Sexual Dysfunction.

PCOS is one of the most common endocrine disorders and NAFLD is one of its most dangerous metabolic consequences. The diagnosis of NAFLD is not a practical task and the condition is at risk of being overlooked. The use of simpler but still reliable surrogate markers is necessary to identify women with a high likelihood of NAFLD. The aim of this study was to evaluate the clinical correlates of NAFLD Liver Fat Score (NAFLD-LFS) in women with oligomenorrhea and/or hirsutism. Furthermore, the study aimed to evaluate whether, among the hormonal parameters evaluated in such women, possible hallmarks of NAFLD may be identified. To this purpose, 66 women who attended our Outpatient Clinic for oligomenorrhea and/or hyperandrogenism were included in the study. In order to validate the results obtained in the first cohort, a second independent sample of 233 women evaluated for female sexual dysfunction (FSD) was analyzed. In cohort 1, NAFLD-LFS positively correlated with metabolic and inflammatory parameters. Among the hormone parameters, NAFLD-LFS showed no significant relationships with androgens but a significant negative correlation with SHBG (p<0.0001) that therefore appeared as a candidate hallmark for pathologic NAFLD-LFS. The ROC analysis showed a significant accuracy (81.1%, C.I.69.1-93.0, p <0.0001) for SHBG in identifying women with a pathological NAFLD-LFS. In particular, a SHBG 33.4 nmol/l was recognized as the best threshold, with a sensitivity of 73.3% and a specificity of 70.7%. In order to validate this SHBG as a marker of metabolic impairment possible related with the presence of NAFLD, we tested this threshold in cohort 2. FSD women with SHBG <33.4 nmol/l had worse metabolic parameters than women with SHBG ≥33.4 nmol/l and a significantly higher NAFLD-LFS even after adjusting for confounders (B=4.18 [2.05; 6.31], p=0.001). In conclusion, this study provides a new evidence in the diagnostic process of NAFLD, showing that the measurement of SHBG, which is routinely assessed in the workup of women referred for possible PCOS, could identify women at higher metabolic risk, thus detecting those who may deserve further targeted diagnostic assessment.

Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis.

STUDY QUESTION: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer? SUMMARY ANSWER: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer. WHAT IS KNOWN ALREADY: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious. STUDY DESIGN, SIZE, DURATION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group. LIMITATIONS, REASONS FOR CAUTION: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: CRD42019153404.

Sphingosine 1-phosphate signaling in uterine fibroids: implication in activin A pro-fibrotic effect.

OBJECTIVE: To explore the link between sphingosine 1-phosphate (S1P) signaling and leiomyoma and the possible S1P cross-talk with the fibrotic effect of activin A. DESIGN: Case-control laboratory study. SETTING: University institute and university hospital. PATIENT(S): Patients with uterine fibroids (n = 26). INTERVENTIONS(S): Tissue specimens of leiomyoma and normal myometrium were obtained from patients undergoing myomectomy or total hysterectomy. MAIN OUTCOME MEASURE(S): Expression of mRNA levels of the enzyme involved in S1P metabolism, S1P receptors, and S1P transporter Spns2 was evaluated in matched leiomyoma/myometrium specimens and cell populations. The effects of inhibition of S1P metabolism and signaling was evaluated on activin A-induced fibrotic action in leiomyoma cell lines. RESULT(S): The expression of the enzymes responsible for S1P formation, sphingosine kinase (SK) 1 and 2, and S1P2, S1P3, and S1P5 receptors was significantly augmented in leiomyomas compared with adjacent myometrium. In leiomyoma cells, but not in myometrial cells, activin A increased mRNA expression levels of SK1, SK2, and S1P2. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P2/3 were blocked. Finally, S1P augmented by itself mRNA levels of fibrotic markers (fibronectin, collagen 1A1) and activin A in leiomyomas but not in myometrial cells. CONCLUSION(S): This study shows that S1P signaling is dysregulated in uterine fibroids and involved in activin A-induced fibrosis, opening new perspectives for uterine fibroid treatment.

Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina.

In this study, we investigated steroidogenic gene mRNA expression in human vaginas and verified the ability of human vagina smooth muscle cells (hvSMCs) to synthesize androgens from upstream precursor dehydroepiandrosterone (DHEA). As a readout for androgen receptor (AR) activation, we evaluated the mRNA expression of various androgen-dependent markers. hvSMCs were isolated from vagina tissues of women undergoing surgery for benign gynecological diseases. In these cells, we evaluated mRNA expression of several steroidogenic enzymes and sex steroid receptors using real time reverse transcription-polymerase chain reaction. Androgen production was quantified with liquid chromatography tandem-mass spectrometry (LC-MS/MS). In vaginal tissues, AR mRNA was significantly less expressed than estrogen receptor α, whereas in hvSMCs, its mRNA expression was higher than progestin and both estrogen receptors. In hvSMCs and in vaginal tissue, when compared to ovaries, the mRNA expression of proandrogenic steroidogenic enzymes (HSD3ß1/ß2, HSD17ß3/ß5), along with 5α-reductase isoforms and sulfotransferase, resulted as being more abundant. In addition, enzymes involved in androgen inactivation were less expressed than in the ovaries. The LC-MS/MS analysis revealed that, in hvSMCs, short-term DHEA supplementation increased Δ4-androstenedione levels in spent medium, while increasing testosterone and DHT secretion after longer incubation. Finally, androgenic signaling activation was evaluated through AR-dependent marker mRNA expression, after DHEA and T stimulation. This study confirmed that the human vagina is an androgen-target organ with the ability to synthesize androgens, thus providing support for the use of androgens for local symptoms of genitourinary syndrome in menopause.

Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence.

RESEARCH QUESTION: How effective is medical hormonal treatment in preventing endometriosis recurrence and in improving women's clinical symptoms and quality of life? DESIGN: This observational cross-sectional study evaluated the effects of hormonal medical treatment (progestins, gonadotrophin-releasing hormone analogues or continuous oral contraceptives) on endometriosis recurrence, current clinical symptoms and quality of life in three groups of patients: Group A (n = 34), no hormonal treatment either before or after the first endometriosis surgery; Group B (n = 76), on hormonal treatment after the first endometriosis surgery; and Group C (n = 75), on hormonal treatment both before and after the first endometriosis surgery. RESULTS: Group C patients were characterized by a lower rate of endometriosis reoperation (P = 0.011) and a lower rate of dysmenorrhoea (P = 0.006). Women who experienced repetitive endometriosis surgery showed worse physical (P = 0.004) and mental (P = 0.012) status than those who received a single surgery, independent of the treatment. CONCLUSION: Hormonal treatments represent a valid cornerstone of endometriosis management and may be useful as an alternative to surgery, but also before surgery, to plan better, and after surgery in order to reduce the risk of recurrence. Medical counselling is very helpful in choosing the correct and individualized endometriosis treatment. In fact, the gold standard for modern endometriosis management is the individualized approach and surgery should be considered, depending on the clinical situation and a patient's symptoms.

Office hysteroscopy in pre- and post-menopausal women: a predictive model.

OBJECTIVES: To assess the variables associated with success of office hysteroscopy (OH) in pre-menopausal and post-menopausal women and to develop a clinical model for predicting the outcome of OH. METHODS: This is a retrospective cohort study of consecutive patients (n = 3181) referred for an OH to a tertiary care university hospital between January 2018 and March 2020. Multivariate logistic regression analysis was used to investigate the variables for predicting the success of OH in all patients and in pre-menopausal and in post-menopausal patients separately. The logistic regression analysis of each variable was applied to develop a predictive model. RESULTS: The overall success rate of the procedure was 92.2%; 95.4% in pre-menopausal women and 87.6% in post-menopausal women. In the general population, independent predictors of procedure success were previous vaginally delivery and hysteroscopy, while previous cervical or uterine surgery were associated with incomplete OH. In the pre-menopausal group, the independent predictors of failure were treatment with GnRH, estroprogestins and infertility. In 89% of cases, our developed model was able to predict whether an OH would be successful in a particular patient. ROC analysis showed an area under the curve of 0.8746 (95% CI: 0.85354-0.89557). CONCLUSIONS: The present study demonstrates the development of a simple and reliable clinical model for the identification of both pre-menopausal and menopausal patients with a high chance of OH success.

Anti-inflammatory effects of androgens in the human vagina.

Chronic inflammation is involved in the genitourinary syndrome of menopause (GSM) and beneficial effects of androgens in the vagina have been described. We investigated the potential involvement of human vagina smooth muscle cells (hvSMCs) in the inflammatory response and the immunomodulatory effect of androgen receptor (AR) agonist dihydrotestosterone (DHT). HvSMCs isolated from menopausal women were evaluated for sex steroids receptors and toll-like receptors mRNA expression, and left untreated or treated in vitro with lipopolysaccharide (LPS) or IFNγ, in the presence or absence of DHT. We evaluated mRNA expression (by RT-PCR) and secretion in cell culture supernatants (by a bead-based immunoassay) of pro-inflammatory markers. Nuclear translocation of NF-κB (by immunofluorescence) and cell surface HLA-DR expression (by flow cytometry) were also evaluated. Similar experiments were repeated in rat vSMCs (rvSMCs). In hvSMCs and rvSMCs, AR was highly expressed. DHT pre-treatment inhibited LPS-induced mRNA expression of several pro-inflammatory mediators (i.e. COX2, IL-6, IL-12A and IFNγ), effect significantly blunted by AR antagonist bicalutamide. DHT significantly counteracted the secretion of IL-1RA, IL-2, IL-5, IL-15, FGF, VEGF and TNFα. LPS-induced NF-κB nuclear translocation was significantly inhibited by DHT, an effect counteracted by bicalutamide. DHT pre-treatment significantly decreased IFNγ-induced expression of HLA-DR, mRNA expression of iNOS, COX2 and MCP1, and secretion of IL-1, IL-2, IL-5, IL-6, MCP1 and GCSF. Similar effects were observed in rvSMCs. The activation of AR suppresses the inflammatory response in hvSMCs, reducing their potential to be involved in the initiation and maintaining of inflammation, thus representing a therapeutic strategy in conditions, such as the GSM.