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One of the most frequent consequences of allogeneic haemopoietic stem cell transplantation (allo-SCT) in both males and females is gonadal insufficiency. We report the case of a 27-year-old myelodysplastic male who developed azoospermia after allogeneic transplantation of haemopoietic stem cells from his HLA-identical sister. Post-transplant azoospermia was alternated with intermittent severe oligospermia. The patient had a normal endocrine pattern and evidence of mild chronic graft-versus-host disease (cGVHD). Normal intratesticular spermatogenesis was revealed by bilateral fine needle aspiration (FNA) cytology. Inflammation was evident at semen analysis, but no infection was detected by microbiological examination and sperm culture. These findings, together with the re-appearance of sperm cells at semen analysis after a low-dose immunosuppressive treatment, suggested the presence of cGVHD of the urogenital tract, causing a reversible obstruction of the spermatic tract and cryptozoospermia. This is the first case report documenting a severe impairment of sperm count because of a reversible obstruction of the seminal tract, likely caused by cGVHD, in a long-term survivor of allo-SCT with normal endocrine pattern. An important practical consequence of this case report is the fact that azoospermia was cured using low-dose immunosuppressive therapy, and this allowed us to avoid expensive stimulatory treatments with gonadotrophins, which remain, however, ineffective if the obstruction of spermatic tracts is not removed. A spontaneous uncomplicated pregnancy occurred in the partner of the patient 3 months after the corticosteroid treatment withdrawal. [ABSTRACT FROM AUTHOR]

BACKGROUND: In ~1214% of young normogonadotrophic women treated with a depot GnRH agonist long protocol, the initial ovarian response to recombinant human FSH (rFSH) can be suboptimal. We have tested the hypothesis that these women may benefit from recombinant human LH (rLH) supplementation in a multicentre, prospective, randomized trial compared with patients treated with an rFSH step-up protocol. METHODS: A total of 260 young normogonadotrophic women undergoing controlled ovarian stimulation with a GnRH agonist long protocol for IVF/ICSI were enrolled. The starting dose of rFSH was 225?IU. One hundred and thirty patients with serum estradiol levels <180?pg/ml and with at least six follicles with a mean diameter >5?mm but none >10?mm on both day 5 and day 8 of stimulation were randomly allocated to two groups. From the eighth day of stimulation, women in group A (n=65) received 150?IU of rLH in addition to rFSH, while those in group B (n=65) had an increase of 150?IU in the daily dose of rFSH (step-up protocol). One hundred and thirty normally responding women continued monotherapy with rFSH and served as a further control population (group C). RESULTS: The mean number of cumulusoocyte complexes retrieved in group A (9.04.3) was significantly higher (P<0.01) compared with group B (rFSH 6.12.6) but significantly lower compared with group C (10.493.7, P<0.05). Implantation and pregnancy rates were significantly lower (P<0.05) in the rFSH step-up group (10.5 and 29.3% respectively) when compared with normal responders (18.1 and 47.3% respectively). CONCLUSIONS: rLH supplementation is more effective than increasing the dose of rFSH in terms of ovarian outcome in patients with an initial inadequate ovarian response to rFSH alone. [ABSTRACT FROM AUTHOR]

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., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background and Objectives: Fractional CO 2 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 CO 2 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 CO 2 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 CO 2 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., (© 2020 Wiley Periodicals LLC.)

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., (Copyright © 2020. Published by Elsevier Inc.)

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 β-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 β-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).

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 (I 2  = 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.

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.

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.

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.

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., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

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., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Atypical polypoid adenomyoma is an uncommon uterine lesion which can coexist with endometrial atypical hyperplasia and/or cancer. Atypical polypoid adenomyoma affects premenopausal women in most cases, but it shows high recurrence rate if conservatively treated. To date, the management of patients is based on low-quality evidence and is not standardized. Our primary aim was to explore the optimal management of atypical polypoid adenomyoma, with particular regard to the fertility-sparing approach. The secondary aim was to define clinicopathologic features of atypical polypoid adenomyoma., Material and Methods: Medline, Embase, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Google Scholar and Cochrane Library were searched for studies reporting outcomes of atypical polypoid adenomyoma treatments. Univariate comparisons among outcomes of fertility-sparing treatments (rates of initial response, progression, recurrence, final complete response, pregnancy) were performed with Fisher's exact test (α = .05)., Results: Eleven retrospective studies with 237 patients were included; 85.5% of patients were premenopausal and 62.9% were nulliparous. Atypical polypoid adenomyoma coexisted with atypical hyperplasia in 5.5% of cases and with endometrial cancer in 5.9%. Overall risks of recurrence and progression to cancer were 28.9% and 16.6%, respectively. Fertility-sparing treatments included hormonal therapy with or without maintenance, hysteroscopic transcervical resection, dilation and curettage, and hormonal therapy combined with transcervical resection or dilation and curettage. Transcervical resection showed significantly higher initial response rates (P from <0.001 to 0.023) than any other treatment. Transcervical resection and transcervical resection+hormonal therapy showed significantly lower progression rates (P < 0.001), and higher final complete response rates (P < 0.001) than any other treatment. No significant differences were found in the rates of pregnancy (P = 0.533 - 0.647) or recurrence (P = 0.052 - 0.475). Among the different transcervical resection techniques, the 4-step transcervical resection showed significantly lower rates of progression (P = 0.002) and recurrence (P = 0.013) than other techniques. Limitations to our results were the retrospective design of the studies and the relatively small sample size, due to the rarity of atypical polypoid adenomyoma., Conclusions: Based on its effectiveness and safety, transcervical resection may be the first-line fertility-sparing treatment for atypical polypoid adenomyoma. In particular, 4-step transcervical resection showed the best results. Given the risk of recurrence, progression and coexistent atypical hyperplasia or cancer, follow-up biopsies are advisable. When fertility preservation is not required, hysterectomy might be advisable., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

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.

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 β -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.

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., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

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.

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.

Study Objective: To evaluate safety and effectiveness of the combination of hysteroscopic endometrial focal resection with levonorgestrel-releasing intrauterine device (LNG-IUD) for International Federation of Gynecology and Obstetrics stage IA G1 early endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) in young women to preserve their fertility., Design: Retrospective case series (Canadian Task Force classification II-3)., Setting: University Federico II, Naples, Italy., Patients: The medical records of 69 consecutive patients treated from 2007 to 2017 with diagnosis of EEC (n = 14) or AEH (n = 55) meeting inclusion criteria were reviewed., Interventions: Patients with focal EEC were treated by hysteroscopic resection of the lesion according to Mazzon's technique; patients with AEH were treated by superficial endometrial resection, preserving the basal layer of the endometrium. An LNG-IUD was inserted in all patients after surgery. Patients were followed for 24 months with serial hysteroscopic biopsies., Measurements and Main Results: Rates of response, live birth, and recurrence were assessed. Of the 14 patients with EEC, 11 (78.6%) achieved a complete response, 2 (18.2%) of whom had subsequent relapse, 1 (7.1%) showed partial response, whereas 2 (14.3%) were nonresponders (1 stable disease and 1 progression). Of the 55 patients with AEH, 51 (92.7%) achieved a complete response, 2 (3.9%) of whom had subsequent relapse, 3 (5.5%) showed partial response, whereas only 1 (1.8%) was nonresponder with stable disease. Among 25 patients who had removed the LNG-IUD, 10 (40%) gave birth after natural conception in the last 12 months of follow-up., Conclusion: The combination of hysteroscopic resection with an LNG-IUD as fertility-sparing treatment of EEC and AEH showed similar response and live birth rates compared with those reported in literature for progestins alone, but with considerably lower relapse rate. We advocate the use of this combined approach as an alternative fertility-sparing option in patients with ECC and AEH., (Copyright © 2018 AAGL. Published by Elsevier Inc. All rights reserved.)

Objectives: CTNNB1 exon 3 mutations have shown independent prognostic value in endometrial cancer. We aimed to assess whether nuclear β-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 β-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 β-catenin is an accurate immunohistochemical surrogate of CTNNB1 exon 3 mutations and thus might be considered in the risk stratification of endometrial cancer., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

Endometrial hyperplasia (EH) is classified into benign and precancerous according to two different histomorphological systems: the World Health Organisation (WHO) system (based on the subjective evaluation of cytological atypia) and the endometrial intraepithelial neoplasia (EIN) system (based on a combination of several parameters that are assessable subjectively, or objectively through computerised analysis). The American College of Obstetricians and Gynecologists recommends use of the EIN system. Nonetheless, a higher prognostic value for EIN criteria was demonstrated only with the objective assessment, which is not routinely applicable. The aim of this study was to evaluate which of the subjective classifications of EH (WHO or EIN) has better prognostic value, by assessing the risk of coexistent cancer. Electronic databases were searched for relevant articles from the inception of the databases to July 2018. All studies assessing the presence of cancer on hysterectomy specimens after a preoperative histological diagnosis of EH were included. Odds ratios (ORs), sensitivity and specificity were calculated with 95% confidence intervals (CIs). Sixteen cohort studies and three case-control studies, assessing 2582 EHs, were included. The WHO criteria showed an OR of 11.15 (95% CI 7.65-16.24), a sensitivity of 0.86 (95% CI 0.82-0.90) and a specificity of 0.67 (95% CI 0.64-0.70) for coexistent cancer. The subjective EIN system showed a similar OR (11.85, 95% CI 4.91-28.62; P = 0.90), higher sensitivity (0.98, 95% CI 0.94-0.99), and lower specificity (0.29, 95% CI 0.24-0.34). The WHO system and the subjective EIN system have similar prognostic values. However, the EIN criteria appear to be more sensitive and thus more suitable for selecting women who need to be treated, whereas the WHO criteria, based on cytological atypia, seem to be more specific for lesions at higher risk of cancer. Therefore, integration of the EIN system with cytological atypia should be considered., (© 2018 John Wiley & Sons Ltd.)

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Introduction: Endometrial hyperplasia may be either a benign proliferation or a premalignant lesion. In order to differentiate these two conditions, two possible histologic classifications can be used: the World Health Organization (WHO) classification and the endometrial intraepithelial neoplasia (EIN) classification. The 2017 European Society of Gynaecological Oncology guidelines recommend the use of immunohistochemistry for tumor suppressor protein phosphatase and tensin homolog (PTEN) to improve the differential diagnosis. Nonetheless, its diagnostic accuracy has never been defined. We aimed to assess the diagnostic accuracy of immunohistochemistry for PTEN in the differential diagnosis between benign and premalignant endometrial hyperplasia., Material and Methods: Electronic databases were searched from their inception to May 2018 for studies assessing immunohistochemical expression of PTEN in endometrial hyperplasia specimens. PTEN status ("loss" or "presence") was the index test; histological diagnosis ("precancer" or "benign") was the reference standard. Sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on summary receiver operating characteristic curves were calculated (95% CI), with a subgroup analysis based on the histologic classification adopted (WHO vs EIN)., Results: Twenty-seven observational studies with 1736 cases of endometrial hyperplasia were included. Pooled estimates showed low diagnostic accuracy: sensitivity 54% (95% CI 50%-59%), specificity 66% (63%-69%), LR+ 1.55 (1.29-1.87), LR- 0.72 (0.62-0.83), DOR 3.56 (2.02-6.28), AUC 0.657. When the WHO subgroup was compared with the EIN subgroup, higher accuracy (AUC 0.694 vs. 0.621), and higher heterogeneity in all analyses, were observed., Conclusions: Immunohistochemistry for PTEN showed low diagnostic usefulness in the differential diagnosis between benign and premalignant endometrial hyperplasia. In the absence of further evidence, the recommendation about its use should be reconsidered., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Benign and precancerous endometrial hyperplasias (EH) are differentiated according to two alternative histomorphologic classifications: World Health Organization (WHO) or endometrial intraepithelial neoplasia (EIN) system. The 2017 European Society of Gynaecological Oncology guidelines recommend paired box 2 protein (PAX2) immunohistochemistry to identify precancerous EH. However, methods for interpreting immunostaining and diagnostic accuracy are not defined, and the role of PAX2 in endometrial carcinogenesis is unclear. We aimed to assess: (a) PAX2 expression throughout endometrial carcinogenesis, from normal endometrium to benign EH, precancerous EH, and endometrial cancer (EC); (b) the diagnostic accuracy of PAX2 immunohistochemistry in diagnosing precancerous EH, defining criteria for its use., Material and Methods: Electronic databases were searched for from their inception to July 2018. All studies evaluating PAX2 immunohistochemistry in normal endometrium, EH, and EC were included. Univariate comparisons of PAX2 expression were performed with Fisher's exact test (significant P < .05). Sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio (DOR), and area under the curve on summary receiver operating characteristic curves were calculated. Subgroup analyses were based on expression thresholds (decrease vs complete loss) and classifications used (WHO vs EIN)., Results: Six studies with 266 normal endometrium, 586 EH, and 114 EC were included. Both decrease and complete loss of PAX2 expression were significantly more common in EC and precancerous EH than benign EH. Diagnostic accuracy was moderate for both PAX2 complete loss and decrease (areas under the curve 0.829 and 0.876, respectively). PAX2 complete loss with EIN system showed the best results (sensitivity = 0.72; specificity = 0.95; DOR = 43.13)., Conclusions: PAX2 seems to behave as a tumor suppressor in endometrial carcinogenesis. PAX2 is an accurate marker of precancerous EH; complete loss of PAX2 and EIN classification appear as the optimal diagnostic criteria., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

The management of patients with a poor ovarian response (POR) to ovarian stimulation represents a challenging issue in reproductive medicine. Apart from economic burdens, the patient with POR has poor prognosis in assisted reproductive technology (ART), which represents a common cause of drop-out from treatment. To introduce a more nuanced picture of POR, the POSEIDON group developed novel criteria to identify and classify patients with low prognosis who undergo ART. The primary goal of POSEIDON criteria is to offer clinicians a pragmatic system to guide therapeutic management with the mindset to obtain the number of oocytes needed for improving ART success. A novel marker of ART success, namely, the ability to obtain the number of oocytes required for achieving at least one euploid embryo for transfer in each patient, is aligned with the POSEIDON criteria. A novel prediction model (ART Calculator) is developed to help clinicians estimate the POSEIDON marker of success. Furthermore, the POSEIDON criteria can also be used to identify more homogeneous populations to test in interventional trials.

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.

Study Objective: Angular pregnancy is a rare and life-threatening condition in which the embryo is implanted in the lateral angle of the uterine cavity, medial to the uterotubal junction and round ligament. Angular pregnancy is associated with a high risk of uterine rupture of about 23% [1]. No consensus has been achieved regarding the diagnostic and therapeutic approach of angular pregnancy [2]. Thus, the aim of this study was to report a case of hysteroscopic treatment of an angular pregnancy in a 34-year-old women., Design: Step-by-step video presentation of the surgical treatment (Canadian Task Force classification III)., Setting: Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy., Patient: A 34-year-old woman. Written informed consent was obtained from the patient., Intervention: Hysteroscopy., Measurements and Main Results: A 34-year-old woman was admitted to our Department with pelvic pain at 6 weeks of gestation. β-Human chorionic gonadotropin (β-hCG) was 5331 mIU/mL. The transvaginal ultrasound showed a gestational sac of 15 × 11 mm in the left uterine angle of an embryo without cardiac activity. The woman opted for a conservative approach with multiple-dose methotrexate [3]. Five days later the β-hCG increased to 7589 mIU/mL with no regression of pregnancy at the transvaginal ultrasound. Therefore, a surgical approach was offered to the patient [4,5]. Laparoscopy showed normal salpinges, whereas hysteroscopy identified the gestational sac in the left uterine angle. A 5Fr bipolar electrode was used to open the gestational capsular decidua. The chorionic villi were progressively separated from the implantation site. Using grasping forceps we removed the specimen for histologic examination. Histologic examination confirmed the diagnosis of angular pregnancy. On the second postoperative day β-hCG was 1131 mIU/mL, and the patient was discharged the day after. At the 1-month follow-up visit, β-hCG and transvaginal ultrasound were negative for pregnancy. The office hysteroscopy showed an empty uterine cavity at 3-months' follow-up., Conclusion: Our case shows that hysteroscopy may be used as a diagnostic and therapeutic tool for angular pregnancy, providing a unique image of the intact removal of the gestational sac., (Copyright © 2018 American Association of Gynecologic Laparoscopists. Published by Elsevier Inc. All rights reserved.)

Air pollution is a cause of concern for human health. For instance, it is associated with an increased risk for cancer, cardiovascular and respiratory disorders. In vitro and in vivo studies suggested that air pollutants could act as endocrine disruptors, promote oxidative stress and exert genotoxic effect. Whether air pollution affects female infertility is under debate. The aim of the present study was to conduct a systematic review of studies that evaluated the impact of air pollution on female infertility. We systematically searched the MEDLINE (PubMed) and SCOPUS databases to identify all relevant studies published before October 2017. No time or language restrictions were adopted, and queries were limited to human studies. We also hand-searched the reference lists of relevant studies to ensure we did not miss pertinent studies. The risk of bias and quality assessment of the studies identified were performed using the Newcastle-Ottawa Scale. Primary outcomes were conception rate after spontaneous intercourse and live birth rate after in vitro fertilization (IVF) procedures. Secondary outcomes were first trimester miscarriage, stillbirths, infertility, number of oocytes and embryo retrieved. Eleven articles were included in the analysis. We found that in the IVF population, nitrogen dioxide and ozone were associated with a reduced live birth rate while particulate matter of 10 mm was associated with increased miscarriage. Furthermore, in the general population, particulate matter of 2.5 mm and between 2.5 and 10 mm were associated with reduced fecundability, whereas sulfur dioxide , carbon monoxide and nitrogen dioxide might promote miscarriage and stillbirths. The main limitation of our findigns resides in the fact that the desegn of studies included are observational and retrospective. Furthermore, there was a wide heterogenity among studies. Although larger trials are required before drawing definitive conclusions, it seems that air pollution could represent a matter of concern for female infertility.

Introduction: Endometrial hyperplasia is differentiated into benign or premalignant. Two histological classifications are used for this purpose: World Health Organization (WHO) classification, based on cytological atypia, disregarding glandular complexity, and endometrial intraepithelial neoplasia (EIN) classification, based on several different parameters. B-cell lymphoma 2 (Bcl-2) loss has been studied as immunohistochemical marker with the aim of improving the differential diagnosis between benign and premalignant hyperplasia. We aimed to evaluate: (A) Bcl-2 loss as marker of endometrial precancer, by assessing it in proliferative endometrium, benign hyperplasia, premalignant hyperplasia, and endometrial cancer; (B) the diagnostic accuracy of Bcl-2 in the differential diagnosis between benign and premalignant endometrial hyperplasia; (c) how the results change according to the histological classification and the thresholds of Bcl-2 expression used., Material and Methods: Electronic databases were searched from their inception to March 2018. All studies assessing Bcl-2 immunohistochemistry in endometrial specimens were included., Results: In total, 20 observational studies assessing 1,278 specimens were included. Bcl-2 loss rates were not significantly different between proliferative endometrium and benign hyperplasia (P = 0.12) and between premalignant hyperplasia and endometrial cancer (P = 0.53). Among hyperplasias, Bcl-2 loss was significantly associated with premalignancy, according to both the WHO (OR = 4.39; P < 0.00001) and EIN classifications (OR = 6.07; P = 0.01), and also with architecture complexity (OR = 2.06; P = 0.02). Using the WHO classification, Bcl-2 loss showed low diagnostic accuracy in detecting premalignant hyperplasia (area under the curve [AUC] = 0.708), with a sensitivity of 0.41, a specificity of 0.81, a positive likelihood ratio of 3.22, and a negative likelihood ratio of 0.69. Using the EIN classification, accuracy was high (AUC = 0.938), with a sensitivity of 0.18, a specificity of 0.97, a positive likelihood ratio of 5.16 and a negative likelihood ratio of 0.86. Thresholds of Bcl-2 expression not involving a complete loss showed lower diagnostic accuracy with a slight increase in sensitivity, but a severe decrease in specificity., Conclusions: B-cell lymphoma 2 loss is a marker of endometrial precancer, with a high specificity and high diagnostic accuracy if the EIN classification is used. Thresholds of Bcl-2 expression not involving a complete loss should not be considered. Bcl-2 loss in endometrial hyperplasia may be a novel indication for treatment when precancerous features are ambiguous in a histological examination. Bcl-2 loss correlates better with EIN classification than with the WHO classification, suggesting that glandular complexity is an important precancerous feature., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Several markers have been studied to predict the responsiveness of endometrial hyperplasia (EH) and early endometrial cancer (EEC) to progestin therapy. PTEN has played a major role in this field, although its predictive significance is still undefined. We aimed to assess if loss of PTEN expression on pre-treatment endometrial specimen may be a predictive markers of response to progestins in EH and EEC., Study Design: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library were searched for relevant articles from the inception to May 2018. All studies assessing PTEN expression as predictive marker in EH and EEC treated with progestin were included. Relative risk (RR) for therapy failure was calculated with 95% confidence interval (CI) and a significant p-value<0.05, with a subgroup analysis based on the histologic category (EEC or EH) and the administration route of progestin (oral or intrauterine)., Results: Seven cohort studies assessing 376 patients were included. PTEN loss was not significantly associated with the outcome of therapy in the overall analysis (RR = 1.24, 95% CI, 0.88-1.76, p = 0.21), in + the subgroups of EEC (RR = 0.89, 0.32-2.49, p = 0.83), EH (RR = 1.30, 0.90-1.87 p = 0.16), oral progestin (RR = 1.25 0.88-1.79, p = 0.22) and intrauterine device (RR = 1.02, 0.36-2.87, p = 0.97)., Conclusion: PTEN seems not to be useful as predictive marker of response to the conservative treatment of EH and EC, regardless of the administration route (oral or intrauterine) of progestins. We advise future researcher not to further assess PTEN as a stand-alone predictive marker., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Morcellation of undiagnosed uterine sarcoma is cause of abdominal/pelvic dissemination, residual tumor and recurrence. In the preoperative evaluation of suspect uterine masses, magnetic resonance imaging (MRI) and serum lactate dehydrogenase (LDH) total activity are referred to as the most effective tools, while computed tomography scan (CT) and LDH isoenzymes are less considered in literature., Case Presentation: A 46 year old woman was admitted to our department with a large uterine mass. Ultrasonography, MRI and LDH total activity did not allow a diagnosis of malignancy, and the woman expressed the wish to avoid hysterectomy. In spite of this, we opted for a total abdominal hysterectomy instead of a laparoscopic myomectomy, due to an elevation of LDH5/LDH1 ratio and CT findings indicative of sarcoma. Histological examination revealed a high grade leiomyosarcoma, confirming our suspicion. Thus, we had avoided the risks linked to morcellation., Conclusions: Our experience suggests that LDH isoenzymes assessment may be relevant in preoperative diagnosis of uterine sarcoma. Further studies are necessary to determine its role in a diagnostic algorithm. We think it may be useful especially for patients with clinical or ultrasonographic suspicion of uterine sarcoma not confirmed by imaging techniques. Furthermore, the role of less considered imaging techniques, such as CT, should not be underestimated in challenging cases.

Hypo-responsiveness to controlled ovarian stimulation is an undervalued topic in reproductive medicine. This phenomenon manifests as a low follicles output rate (FORT) with a discrepancy between the relatively low number of pre-ovulatory follicles which develop following ovarian stimulation as compared to the number of antral follicles available at the start of stimulation. The pathophysiology mechanisms explaining the ovarian resistance to gonadotropin stimulation are not fully understood, but the fact that both hypo-responders and normal responders share similar phenotypic characteristics suggests a genotype-based mechanism. Indeed, existing evidence supports the association between specific gonadotropin and their receptor polymorphisms and ovarian hypo-response. Apart from genotypic trait, environmental contaminants and oxidative stress might also be involved in the hypo-response pathogenesis. The ratio between the number of oocytes collected at the ovum pick up and the number of antral follicles at the beginning of OS [Follicle to oocyte index (FOI)] is proposed as a novel parameter to assess the hypo-response. Compared with traditional ovarian reserve markers, FOI might reflect most optimally the dynamic nature of follicular growth in response to exogenous gonadotropin. In this review, we contextualize the role of FOI as a parameter to identify this condition, discuss the underlying mechanisms potentially implicated in the pathogenesis of hypo-response, and appraise possible the treatment strategies to overcome hyper-responsiveness to gonadotropin stimulation.