The relevance of prothrombotic genetic variants in women who experienced pregnancy loss or embryo implantation failure: A retrospective analysis of 1922 cases.

OBJECTIVE: The aim of our study was that to assess the allelic and genotype frequencies of nine prothrombotic gene variants in patients with a history of pregnancy loss and recurrent pregnancy loss (RPL). Women who underwent assisted reproductive technology (ART) with ongoing pregnancy and those with recurrent implantation failure (RIF) were also included. METHODS: Nine prothrombotic gene variants were evaluated: factor V Leiden (FVL), factor V, H1299R variant (FVR2), factor II (FII) G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, beta-fibrinogen -455G>A, factor XIII (FXIII) V34L, human platelet antigen-1 (HPA-1) L33P variants, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G. The following study groups were assessed: (1) women who experienced one (n = 334) or two (n = 264) episodes of pregnancy loss; (2) 468 women who experienced RPL; (3) 214 women who underwent ART followed by ongoing pregnancies; and (4) 282 women who experienced RIF after ART, that is, three or more consecutive implantation failures following high-quality embryo transfers to the uterus with an appropriate endometrium. As control group, 430 subjects from the general population were enrolled. RESULTS: FVL, the -455G>A variant of beta-fibrinogen, and PAI-1 4G were associated with a higher risk of developing RPL compared with the general population. Furthermore, FVL, FVR2, FII G20210A and MTHFR C677T conferred a significantly higher risk of RIF in women who performed ART compared with the general population. No statistical differences between the general population and other study groups were observed. CONCLUSIONS: Specific prothrombotic genetic variants are more frequently expressed in women with RPL and RIF, supporting their role in the development of polimicrothrombosis and impairing the invasion during embryo implantation.

Comparison of Virtual Ultrasonographic Hysteroscopy with Conventional Hysteroscopy in the Workup of Patients Who Are Infertile.

STUDY OBJECTIVE: To compare the tolerability and diagnostic accuracy of virtual ultrasonographic hysteroscopy (VUH) with that of conventional diagnostic outpatient hysteroscopy in the workup of patients who are infertile. DESIGN: A single-center, retrospective cohort study. SETTING: Department of Obstetrics and Gynecology, Gynecologic Oncology, and Minimally Invasive Pelvic Surgery Unit of Sacred Heart Hospital Don Calabria in Negrar, Italy. PATIENTS: A total of 120 consecutive women who underwent hysterosalpingosonography and subsequent VUH and conventional hysteroscopy for infertility evaluation were included. The inclusion criterion was infertility for at least 1 year, with evaluation in the early or intermediate follicular phase of the menstrual cycle. INTERVENTIONS: After the placement of an intracervical catheter, a Ringer Lactate solution was injected into the uterine cavity and fallopian tubes, and a 3D volume was obtained. The ultrasound volume acquired was successively elaborated offline, and a VUH was performed. Subsequently, a variable amount of air was introduced into the uterine cavity, and the patency of the salpinges was evaluated. MEASUREMENTS AND MAIN RESULTS: The VUH findings were compared with those of conventional hysteroscopy performed in the subsequent month. For the detection of endometrial pathology in the overall pool, the sensitivity and specificity of VUH in comparison with conventional hysteroscopy were 100% (95% confidence interval [CI], 84.6%-100%) and 100% (95% CI, 96.3%-100%), respectively. For the detection of uterine cavity pathology and uterine malformations in the overall pool, the sensitivities of VUH were 80% (95% CI, 28.4%-99.5%) and 100% (95% CI, 75.3%-100%), respectively, with specificities of 100% (95% CI, 96.8%-100%) and 100% (95% CI, 96.6%-100%), respectively, when compared with conventional hysteroscopy. The positive predictive values for endometrial pathology, uterine cavity alterations, and uterine malformations were 100% (95% CI, 84.6%-100%), 100% (95% CI, 39.8%-100%), and 100% (95% CI, 75.3%-100%), respectively, with a receiver operating characteristic area of 100%, 90% (95% CI, 70%-100%), and 100%, respectively. There were no cases of severe vasovagal reactions or other complications. Most patients (67%, 81 of 120 women) described the examination as "less painful than expected," 25% (30 of 120 women) "just as expected," and only 7% (9 of 120 women) as "more painful than expected." CONCLUSION: VUH was well tolerated and showed a high accuracy (100%) in the study of the uterine cavity when compared with conventional hysteroscopy.

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.

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.

Diabetes Mellitus Is Associated with Occult Cancer in Endometrial Hyperplasia.

In the management of women diagnosed with endometrial hyperplasia (EH), it is crucial to determine the risk of coexistent cancer. Diabetes mellitus has been recently suggested as a significant risk factor. However, results in this regard are conflicting. Our aim was to assess the association between diabetes mellitus and coexistent cancer in women diagnosed with endometrial hyperplasia. A systematic review and meta-analysis was performed by searching electronic databases from their inception to October 2018 for studies assessing the presence of coexistent cancer after a preoperative diagnosis of endometrial hyperplasia in women stratified for diabetes mellitus. Odds ratio was calculated with 95% confidence interval; a p value <0.05 was considered significant. Twelve retrospective studies with 1579 EH were included. Diabetes mellitus showed significant association with the presence of cancer coexistent with endometrial hyperplasia (OR = 1.96; 95% CI, 1.07-3.60; p = 0.03). Heterogeneity among studies was moderate (I2 = 55%). Funnel plot showed asymmetric distribution of OR values, with the large and accurate studies showing results stronger than small and less accurate one; this finding should exclude a publication bias. In women diagnosed with endometrial hyperplasia, diabetes mellitus is a risk factor for coexistent cancer, and thus may be included in a predictive algorithm for the risk stratification. In women conservatively treated, glycemic control may be required to prevent the risk of progression. Further studies are necessary to confirm the clinical significance of diabetes mellitus in this field.

Immunophenotype of Atypical Polypoid Adenomyoma of the Uterus: Diagnostic Value and Insight on Pathogenesis.

Atypical polypoid adenomyoma (APA) is a rare uterine lesion constituted by atypical endometrioid glands, squamous morules, and myofibromatous stroma. We aimed to assess the immunophenotype of the 3 components of APA, with regard to its pathogenesis and its differential diagnosis. A systematic review was performed by searching electronic databases from their inception to January 2019 for immunohistochemical studies of APA. Thirteen studies with 145 APA cases were included. APA glands appeared analogous to atypical endometrial hyperplasia (endometrioid cytokeratins pattern, Ki67≤50%, common PTEN loss, and occasional mismatch repair deficiency); the prominent expression of hormone receptors and nuclear ß-catenin suggest that APA may be a precursor of "copy number-low," CTNNB1-mutant endometrial cancers. Morules appeared as a peculiar type of hyperdifferentiation (low KI67, nuclear ß-catenin+, CD10+, CDX2+, SATB2+, p63-, and p40-), analogous to morular metaplasia in other lesions and distinguishable immunohistochemically from both conventional squamous metaplasia and solid cancer growth. Stroma immunphenotype (low Ki67, α-smooth-muscle-actin+, h-caldesmon-, CD10-, or weak and patchy) suggested a derivation from a metaplasia of normal endometrial stroma. It was similar to that of nonatypical adenomyoma, and different from adenosarcoma (Ki67 increase and CD10+ in periglandular stroma) and myoinvasive endometrioid carcinoma (h-caldesmon+ in myometrium and periglandular fringe-like CD10 pattern).

Significant risk of occult cancer in complex non-atypical endometrial hyperplasia.

BACKGROUND: In the 2014 WHO classification of endometrial hyperplasia (EH), complex EH is lumped together with simple EH in the benign category of non-atypical EH. OBJECTIVE: To assess the risk of coexistent cancer in complex EH and simple EH without atypia, through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to January 2019 for relevant articles. RESULTS: Twelve studies assessing a total of 804 non-atypical EH were included. The risk of coexistent cancer was significantly higher in complex EH (12.4%) than in simple EH (2%), with an OR of 6.03 (p = 0.0002). CONCLUSION: Even in the absence of cytologic atypia, complex EH is associated with a significant risk of coexistent cancer. Further studies are necessary to investigate the need for a revision in the WHO classification.

Pharmacogenetics of FSH Action in the Female.

The purpose of a pharmacogenomic approach is to tailor treatment on the basis of an individual human genotype. This strategy is becoming increasingly common in medicine, and important results have been obtained in oncologic and antimicrobial therapies. The rapid technological developments and availability of innovative methodologies have revealed the existence of numerous genotypes that can influence the action of medications and give rise to the idea that a true "individualized" approach could become in the future a reality in clinical practice. Moreover, compared to the past, genotype analyses are now more easily available at accessible cost. Concerning human reproduction, there is ample evidence that several variants of gonadotropins and their receptors influence female reproductive health and ovarian response to exogenous gonadotropins. In more detail, variants in genes of follicle-stimulating hormone ß-chain (FSH-B) and its receptor (FSH-R) seem to be the most promising candidates for a pharmacogenomic approach to controlled ovarian stimulation in assisted reproductive technologies. In the present review, we summarize the evidence regarding FSH-B and FSH-R variants, with special reference to their impact on reproductive health and assisted reproductive technology treatments.

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin.

POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4-9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

Diabetes mellitus and responsiveness of endometrial hyperplasia and early endometrial cancer to conservative treatment.

Objective: The conservative treatment of endometrial hyperplasia without atypia (HWA), atypical endometrial hyperplasia (AH/EIN) and early endometrioid carcinoma (EEC) is based on progestins. We aimed to assess whether diabetes mellitus affects the responsiveness of HWA, AH/EIN and EEC to conservative treatment, through a systematic review and meta-analysis. Study design: Electronic databases were searched for studies assessing the outcome of conservative treatment in HWA, AH/EIN and EEC, stratified based on the diagnosis of diabetes mellitus. The association of diabetes mellitus with treatment failure was assessed by using odds ratio (OR). A p-value < .05 was considered significant. The risk of publication bias was assessed by using a funnel plot. A subgroups analyses was performed based on histologic diagnosis of benignity (HWA) or premalignancy/malignancy (AH/EIN or EEC). Results: Six studies with 876 patients (383 HWA, 365 AH/EIN and 128 EEC) were included. Overall, diabetes mellitus was not associated with outcome of treatment (OR = 1.20; p = .62). The association was not significant in both the HWA subgroup (OR = 0.95; p = .93) and in AH/EIN and EEC subgroup (OR = 1.43; p = .46). There was no significant risk of publication bias. Conclusions: Diabetes mellitus does not affect the outcome of conservative treatment in HWA, AH/EIN and EEC.

Correction to: The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis.

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PTEN expression in endometrial hyperplasia and risk of cancer: a systematic review and meta-analysis.

PURPOSE: Rates of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) are highly variable. Among several prognostic markers, PTEN has been recommended by ESMO-ESGO-ESTRO to identify premalignant EH. However, its prognostic accuracy is unclear. Thus, we aimed to assess: (1) the association between PTEN loss in EH and risk of cancer, and (2) the prognostic accuracy of PTEN immunohistochemistry in EH. METHODS: Electronic databases were searched from their inception to June 2018. All studies assessing PTEN immunohistochemistry in EH and the presence of EC on subsequent hysterectomy were included. Odds ratio (OR), sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) and area under the curve (AUC) on SROC curves were calculated with subgroup analysis (short/long-term; atypical/non-atypical EH). RESULTS: Nine retrospective studies assessing 933 EH were included. PTEN loss in EH was significantly associated with increased risk of EC (OR = 3.32, p = 0.001). The association was significant only on the short term ( < 1 year) (OR = 3.45, p = 0.002) and in atypical EH (OR = 1.89, p = 0.01). For overall analysis and short-term/atypical EH subgroup the prognostic accuracy was low, with sensitivity = 0.58 and 0.68, specificity = 0.60 and 0.48, VPp = 0.41 and 0.54, VPN = 0.75 and 0.63, LR + = 1.80 and 1.37, LR - = 0.62 and 0.56, AUC = 0.687 and 0.721, respectively. CONCLUSION: PTEN loss in EH is a risk factor for EC, but is not reliable in predicting the risk of EC. In atypical EH, PTEN loss is associated with a risk of concurrent EC of over 50%. This information might integrate the patients' informed consent for the choice of treatment (conservative/hysterectomy), especially in borderline cases. In conservative approach, PTEN loss might suggest closer follow-up.

Endometrial hyperplasia and progression to cancer: which classification system stratifies the risk better? A systematic review and meta-analysis.

PURPOSE: Benign and precancerous endometrial hyperplasias (EH) are differentiated thorough two possible histomorphologic classifications: WHO (adopting the subjective evaluation of cytologic atypia) and EIN (adopting several histomorphologic parameters, evaluable subjectively, or objectively with a computerized analysis calculating a prognostic score, the D score). ACOG recommends the use of EIN system although no distinction was made between objective assessment (not widely available), and subjective assessment (more applicable in the common practice). Moreover, it is still unclear if subjective EIN system is actually preferable to WHO classification. We aimed to assess the reliability of WHO system, D score and subjective EIN system in stratifying the risk of progression to cancer in EH. METHODS: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Cochrane Library and Google Scholar were searched for relevant articles from the inception to August 2018. All studies assessing the rates of progression of EH to cancer were included. RESULTS: Twelve cohort studies and one case-control study, assessing 3629 EH, were included. Relative risk (RR) for cancer progression was calculated with 95% confidence interval (CI), and results were compared using Chi-square test (significant p value < 0.05). WHO system showed a RR of 8.74 (95% CI 6.66-11.47). Objective D score showed a RR of 29.22 (95% CI 13.24-64.51), significantly higher than WHO (p = 0.005). Subjective EIN system showed a RR of 19.37 (95% CI 5.86-64.01), intermediate between WHO and D score, without significant differences (p = 0.20 and p = 0.57, respectively). CONCLUSION: Objective EIN criteria with D score are significantly more reliable than WHO criteria in stratifying the risk of progression of EH to cancer. Subjective EIN criteria did not show significant superiority over WHO instead. Further studies are necessary to determine if subjective EIN system should replace WHO system in the routine diagnosis of EH.

Immunohistochemical predictive markers of response to conservative treatment of endometrial hyperplasia and early endometrial cancer: A systematic review.

INTRODUCTION: Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer. MATERIAL AND METHODS: Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse. RESULTS: Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9. CONCLUSIONS: Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel.

PTEN immunohistochemistry in endometrial hyperplasia: which are the optimal criteria for the diagnosis of precancer?

Guidelines recommend protein phosphatase and tensin homolog (PTEN) immunohistochemistry for differentiating between benign endometrial hyperplasia (BEH) and atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). However, it is unclear when PTEN expression should be defined as 'lost' and thus suggestive of AEH/EIN. We aimed to determine the optimal immunohistochemical criteria to define PTEN loss in endometrial hyperplasia, through a systematic review and meta-analysis of diagnostic accuracy. Electronic databases were searched for studies assessing immunohistochemical expression of PTEN in both BEH and AEH/EIN specimens. PTEN status ('loss' or 'presence') was the index test; histological diagnosis ('AEH/EIN' or 'BEH') was the reference standard. Accuracy was quantified based on the area under the curve (AUC) on summary receiver operating characteristic (SROC) curves, for several different thresholds of PTEN expression. Eighteen studies with 1362 hyperplasias were included. Six different criteria to define PTEN loss were assessed. Low diagnostic accuracy was found for complete loss of expression (AUC = 0.71), presence of any null gland (AUC = 0.63), positive cells <10% (AUC = 0.64), positive cells <50% (AUC = 0.71) and moderate-to-null intensity (AUC = 0.64). Barely moderate diagnostic accuracy was only found for the subjective criterion 'weak-to-null intensity' (AUC = 0.78). Therefore, the clinical usefulness of PTEN immunohistochemistry in this field should be further investigated.

Should progesterone and estrogen receptors be assessed for predicting the response to conservative treatment of endometrial hyperplasia and cancer? A systematic review and meta-analysis.

INTRODUCTION: Progestins are used as conservative treatment of endometrial hyperplasia (EH) and early endometrial cancer (EEC). We aimed to assess whether immunohistochemical expression of estrogens and progesterone receptors (ER and PR) predicts the treatment response. MATERIAL AND METHODS: Electronic databases were searched for studies assessing ER and PR expression in EH and EEC treated with progestins. Relative risk for poor response, sensitivity, specificity, diagnostic odds ratio positive and negative likelihood ratios (LR+ and LR- ) and area under the curve (AUC) on summary receiver operating characteristic curve were calculated. Subgroup analyses were based on administration route (oral progestin or levonorgestrel-intrauterine device) and on histological diagnosis (atypical EH/EEC or non-atypical EH). Only high accuracy (AUC > 0.9; LR+  >10; LR-  <0.1) was considered determining for the clinical practice. RESULTS: Thirteen studies with 635 patients were included in the systematic review. Studies at high risk of bias were excluded from the meta-analysis. Negative ER expression did not significantly predict poor response (P = 0.16), with low predictive accuracy (AUC = 0.637). Negative PR significantly predicted poor response (P = 0.01), with moderate accuracy (AUC = .806). In the oral progestin subgroup, neither ER (P = 0.55) nor PR (P = 0.18) had significant predictive value. In the levonorgestrel-intrauterine device subgroup, both ER (P < 0.0001) and PR (P = 0.02) were significantly predictive of good response, although the accuracy was suboptimal (LR+ 6.02 and 2.48, respectively; LR- 0.59 and 0.55, respectively). The atypical EH/EEC subgroup showed non-significant results. Data about non-atypical EH were not extractable. CONCLUSIONS: ER and PR expressions are significantly predictive of response in EH and EEC treated with a levonorgestrel-intrauterine device but not with oral progestins. However, their accuracy is insufficient to be determining in the clinical practice.

The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis.

OBJECTIVE: To study the role of recombinant human LH supplementation in women with hypo-response to ovarian stimulation. METHODS: We performed a systematic review and meta-analysis of prospective clinical trials in which recombinant FSH monotherapy protocols were compared with LH-supplemented protocols in hypo-responders. A search was conducted of the Scopus, MEDLINE databases without time or language restrictions. Primary outcome was clinical pregnancy rate. RESULTS: Significantly higher clinical pregnancy rates (odds ratio: 2.03, P = 0.003), implantation rates (odds ratio: 2.62, P = 0.004) and number of oocytes retrieved (weight mean differences: 1.98, P = 0.03) were observed in hypo-responders supplemented with recombinant LH versus hypo-responders who underwent FSH monotherapy. No differences in terms of mature oocytes or miscarriage rates were found between the two groups. CONCLUSION: In conclusion, our analysis confirms that women with a hypo-response to exogenous gonadotropins might benefit from LH supplementation. However, more trials are required before a definitive conclusion can be drawn.

Complexity of glandular architecture should be reconsidered in the classification and management of endometrial hyperplasia.

The 2014 World Health Organization (WHO) classification of endometrial hyperplasia (EH) defines premalignant EH based on only cytologic atypia, disregarding architecture complexity. We aimed to assess the impact of architecture complexity on the risk of cancer in non-atypical EH. A systematic review and meta-analysis was performed by searching electronic databases form their inception to October 2018. All studies assessing the rates of progression to cancer in non-atypical EH (simple vs complex) were included. Pooled relative risk (RR) for cancer progression was calculated; a p-value < 0.05 was considered significant. Eight studies with 1066 women were included. The risk for progression of non-atypical EH to cancer was significantly higher in complex EH than in simple EH (p < 0.0001), with an RR of 4.90. In conclusion, the complexity of glandular architecture significantly increases the risk of cancer in non-atypical EH. Complex non-atypical EH may be regarded as a low-risk premalignant lesion rather than a benign condition.

Immunohistochemical Nuclear Expression of ß-Catenin as a Surrogate of CTNNB1 Exon 3 Mutation in Endometrial Cancer.

OBJECTIVES: CTNNB1 exon 3 mutations have shown independent prognostic value in endometrial cancer. We aimed to assess whether nuclear ß-catenin expression is an accurate surrogate, as immunohistochemistry is cheaper, faster, and more widely applicable than sequencing. METHODS: A systematic review was performed by searching electronic databases for all studies assessing the association between ß-catenin immunohistochemical expression and CTNNB1 mutations. Meta-analysis of diagnostic accuracy was performed by calculating sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on summary receiver operating characteristic curves. RESULTS: Fifteen observational studies with 1,158 endometrial carcinomas were included. Pooled estimates showed sensitivity = 0.88, specificity = 0.85, LR+ = 4.57, LR- = 0.20, DOR = 27.16, and high diagnostic accuracy (AUC = 0.91). CONCLUSIONS: Nuclear expression of ß-catenin is an accurate immunohistochemical surrogate of CTNNB1 exon 3 mutations and thus might be considered in the risk stratification of endometrial cancer.